Process for preparing benzodiazepine derivatives

ABSTRACT

THE PROCESS FOR PRODUCING BENZODIAZEPINE DERIVATIVES USEFUL FOR TRANQUILIZER,   1-R1,5-(X-PHENYL),R2,1,2-DIHYDRO-3H-1,4-BENZODIAZEPIN-2-   ONE   WHEREIN R1 IS HYDROGEN, C1-C3 ALKYL GROUP OR C4-C7 CYCLOHEXYLMETHYL GROUP AND R2 IS HYDROGEN OR HALOGENS AND X IS HALOGENS. 2-AMINOO-METHYLINDOLE DERIVATIVES OR THEIR SALTS 1-R1,2-(H2N-CH2-),3-(X-PHENYL),R2-INDOLE WHEREIN R1, R2 AND X RESPECTIVELY HAVE THE SAME MEANINGS AS ABOVE IS ALLOWED TO REACT WITH AN APPROPRIATE OXIDIZING AGENT, SUCH AS FOR EXAMPLE, CHROMIUM TRIOXIDE.

United States Patent 3,828,027; PROCESS FOR PREPARING BENZODIAZEPINEDERIVATIVES Hisao Yamamoto and Shigeho Inaba, Nishinomiya-shi, TadashiOkarnoto, Ashiya-shi, Toshiyuki Hirohashi, Kobe, Kikuo Isbizumi,Minoo-sh'i, Michihiro Yamamoto, Takarazuka-shi, Isamu Maruyama,Minoo-shi, Kazuo Mori, Kobe, and Tsuyoshi Kobayashi, Minooshi, Japan,assignors to SumitomoChemical Company, Ltd., Osaka, Japan No Drawing.Filed Sept. 16, 1968, Ser. No. 762,341 Claims priority, applicationJapan, Sept. 22, 1967, 42/60,952; Sept. 27, 1967, 42/62,424, 42/62,425,.42/62,426, 42/62,427, 42/62,428, 42/62,429, 42/62,630; Oct. 9, 1967,42/65,102, 42/65,104; Oct. 18, 1967, 42/ 67,354; Nov. 2, 1967, 42/70,794, 42/70,796, 42/70,798; Nov. 6, 1967, 42/71,598; Nov. 8, 1967,42/72,078; Dec. 9, 1967, 42/79,166; Dec. 15, 1967, 42/80,514; Dec. 21,1967, 42/ 82,273; Jan. 10, 1968, 43/1,501 The portion of the term of thepatent subsequent to Jan. 26, 1988, has been disclaimed Int. Cl.C07d53/06 US. C]. 2611-2393 D Claims ABSTRACT on" THE DISCLOSURE Theprocess for producing benzodiazepine derivatives useful fortranquilizer,

wherein R is hydrogen, C -C alkyl group or C -C cyclohexylmethyl groupand R is hydrogen or halogens and X is halogens.

Z-Amino-methylindole derivatives or their salts wherein R R and Xrespectively have the same meanings as above is allowed to react with anappropriate oxidizing agent, such as for example, chromium trioxide.

wherein R represents a hydrogen atom, a lower alkyl group having 1-3carbon atoms or a cycloalkylmethyl having 4-7 carbon atoms, and Rrepresents a hydrogen atom or a halogen atom, and X represents a halogenatom.

That is, the invention relates to a process, according to whichbenzodiazepine derivatives represented by theformula [I] are readilyobtained by reacting 2-aminomethylindole derivatives represented by theformula [II] or their salts wherein R R and X respectively have the samemeanings as defined above, or their salts with an appropriate oxidizingagent.

The benzodiazepine derivatives represented by the formula [I] are knownas a remarkably effective tranquilizer, muscle relaxant, anti-convulsantand hypnotic.

A few processes for producing the benzodiazepine derivatives have beendescribed. For instance, which is one of the most useful procedures bynow, a benzodiazepine derivative is obtained in a poor yield by reactinga 2- aminobenzophenone derivative with glycine hydrochloride or glycineethyl ester (German Pat. 1,145,626).

A benzodiazepine derivative is also prepared by treating achloroacetamidobenzophenone with ammonia. [Sternbach et al.: Journal ofOrganic Chemistry 27, 3788 (1962) and German Pat. 1,136,709.]

On the contrary to these procedures, to our astonishment, we have foundthat a benzodiazepine derivative having the formula [I] can be preparedsmoothly and economically in high yield and in high purity by reacting a2 aminomethyl-indole derivative having the formula [II] or their saltwith an appropriate oxidizing agent. Such surprising process from a5-membered ring compound to a 7-membered ring compound due to ringexpansion reaction has not heretofore been described in any literature.Therefore, the novel process of the present invention is unobvious fromthe known method of the similar processes, and moreover very much usefuland unexpected procedure.

These novel starting materials, 2-aminoethylindole derivatives wereprepared easily by the reduction of indole- 2-carboxamide derivatives orindole-2-carbonitrile derivatives. 4

These indole-2-carboxamide derivatives are also novel compounds, whichwere prepared by the amidation of indole-2-carboxylic acid derivativesin good yield. Further, the indole-2-carboxylic acid derivatives arenovel, which is obtained, for example, by the cyclization of benzenellIl diazonium compounds with ester derivatives of a-benzyl- 1 All ofthese processes proceed smoothly and give the objective products in highyield, so these procedures are very much useful in practice.

One object of the present invention is to provide a novel process forpreparing benzodiazepine derivatives represented by the formula [I].

Another object is to provide a novel process for producing the salts ofbenzodiazepine derivatives by treating the benzodiazepine derivatives ofthe formula [I] with a mineral acid such as hydrochloric acid, sulfuricacid, nitric acid, phosphoric acid, and the like, or organic acid suchas maleic acid, fumaric acid, succinic acid, formic acid, or aceticacid, and the like.

A further object of the present invention is to provide novel indolederivatives, novel phenylhydrazone derivatives and benzene diazoniumderivatives and process for preparing the same.

Other objects of the present invention will be apparent from thefollowing description.

In order to accomplish these objects, the present invention provides aprocess for preparing benzodiazepine derivatives represented by theformula [I], which comprises reacting a Z-aminomethylindole derivativerepresented by the formula [II] or its salt with an oxidizing agent.

Further the present invention provides a process for producing salts ofbenzodiazepine derivatives of the formula [I], which comprises reactinga Z-aminomethylindole derivative of the formula [H] or its salt with anoxidizing agent to yield the benzodiazepine derivative of the formula[I] and reacting the benzodiazepine derivative of the formula [I] with amineral acid such as hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid, or organic acid such as maleic acid, fumaric acid,succinic acid, formic acid, acetic acid, and the like.

Still further, the present invention provides novel phenylhydrazonederivatives and benzene diazonium derivatives and a process forproduction thereof.

Furthermore, the present invention provides novel indole derivatives,that is, Z-aminomethylindole derivatives, indole 2 carbonitrilederivatives, indole-Z-carboxamide derivatives, indole 2 carboxylic acidderivatives, and a process for production thereof.

In carrying out the process for preparing the benzodiazepine derivativesaccording to the present invention, 2- aminomethylindole derivativesrepresented by the formula [II] or their salts are reacted with anappropriate oxidizing agent, for example, ozone, hydrogen peroxide,peracid (eg performic acid, peracetic acid and perbenzoic acid), chromicacid and potassium permanganate. The oxidizing agent used in the processof the invention is not limited, however, only to those exemplifiedabove. The reaction is generally readily effected at room temperature.Higher or lower temperature is sometimes found more satisfactory.

Chromium trioxide is preferred as oxidizing agent. The reaction maypreferably be carried out in the presence of a solvent. The solventdepends upon the oxidizing agents used, and is selected from water,acetone, carbon tetrachloride, acetic acid, sulfuric acid and any othersolvents which do not react substantially with any of the reactants. Theoxidizing agent is used in a stoichiometric amount or more. The reactiontemperature used depends upon the oxidizing agent used.

In the case which the oxidation is carried out using chromium trioxidein the presence of acetic acid, it is preferable to use 2-3 times astoichiometric amount of chromium trioxide and to conduct the reactionat room temperature. A 2'aminomethylindole derivative or its salt suchas hydrochloride, hydrobromide, sulfate, nitrate, acetate and the likeis dissolved or suspended in a solvent and an oxidizing agent is addedthereto with stirring. The reaction is generally completed within about24 hours.

t The desired benzodiazepine derivative can be separated from thereaction mixture in a crude form by extraction after neutralization orwithout neutralization and by evaporation to dryness. The product maybefurther purified, if desired, by recrystallization from an appropriatesolvent such as ethanol, isopropanol and the like in a standard manner.2

Thus, for example, the invention includes benzodiazepine derivativessuch as v -(o-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine- 2-one, 5-(o-iluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine 2-one, I v V i i a 5-(o-chlorophenyl)-7-chloro-1,3-dihydro-2H-l,4 benzo- -diazepine 2-one, i5-(o-fiuorophenyl)-7-chloro-1,3-dihydro-2H-l,4-benzo diazepine-Z-one, i

S-(o-bromophenyl)-7-chloro 13-dihydro-2H- diazepine-Z-one, 5-(m-chlorophenyl) -7-chloro -l ,3 -dihydro-2H- 1 ,4-

benzodiazepine-Z-one, f; S-(p-chlorophenyl) -7-bromo-l,3-dihydro-2H-1,4-benzodiazepine-Z-one, l-methyl-S- (o-chlorophenyl) "lschloro l ,3-dihydro,-2l -I-.; 1,4-benzodiazepine-2-one, l-methyl-S-(o-fluorophenyl) -7:chloro.- l,3-dihydro2H 1,4-benzodiazepine-2-one,l-methyl-S- o-fiuorophenyl-7-brorno- 1,3-d

1,4-benzodiazepine-2roneJ I 1-ethyl-5-(o-fiuorophenyl)-7chloro-1,3:dihydro H 1,4benzodiazepine-2-one,"l-propyl-S-(o-fluorophenyl) 7-chlor o-1, dihydro 2H-.1,4-benzodiazepine-2 one, f 1- l-cyclopropylmethyl-S- (o-fluorophenyl)'r 1,3 -d ihydro-2H- l,4-benzodiazepine-2-one, i1-cyclopropylmethyl-5-(o-chlorophenyl)1,3 dihydro-2H-1,4-benzodiazepine-2-one,- 1-cyclopropylmethyl-5- (o fluorophenyl)-7-ch1oro-l ,3-

dihydro-2H-1,4-benzodiazepine-2-one, 41-cyclopentylmethyl-5-(odiuorophenyl -7-chloro-1,3dihydro-2,H-1,4-benzodiazepine-2 one,

l-cyclopropylmethyl-S- (o-chlorophenyl) 7 -chloro- 1,3-

dihydro-ZH-l,4-benzodiazepine-2 one,l-cyclopropylmethyl-S-(o-fiuorophenyl)-9echloro 1,3-

dihydro-ZH-l,4-benzodiazepine-2 one, l-cyclopropyl;nethyl-5(o-fluorophenyl).-7-brqrno;l,3- dihydro-ZH-1,4-benzodiazepine-2-one, il-cyclobutylmethyl-S-(o-fluorophenyl)-7-chloro-1,3-dihydro-ZI-I-l,4-benzodiazepine-2-one,l-cyclopentylmethyl-S-(o-fiuorophenyl)-7-bromo-l,3-

dihydro-ZH-1,4-benzodiazepine-2-one, andl-cyclohexylmethyl-S-(o-fluorophenyl)-7-chloro-l,3-

dihydro-ZH-1,4-benzodiazepine-2-one.

At the first step for producing the 2 aminomethylindole derivatives[II], a phenylhydrazone derivative represented by the formula [V] n, R1(13H;

u. 2. .1 wherein R R and X respectivelyhave the same meanings as definedabove and R represents a hydrogen atom," an alkyl group having 1-4carbon atoms or a benzyl group, is readily obtained by reacting aphenylpyruvicacid deriyative represented by the formula [III],v v

wherein R and X have the same meaning as defined above, with aphenylhydrazine derivative represented by the formula [IV] or its saltwherein R and R respectively have the same meanings as defined above. a

wherein R and X have the same meanings as defined above and R representsan alkyl having 1-4 carbon atoms or benzyl group, by reacting esterderivatives of fi-keto acid represented by the formula [VH] n oo-erhooome [VII] wherein R represents an alkyl group having 14 carbon atoms and'Rand X have the same meanings as defined above, with a benzene diazoniumsalt represented by the formula [VIII] t v R3 [VIII] wherein Zrepresents a halogen atom and R has the same meaning as defined above.In this reaction, novel azo derivatives represented by the formula[XXII] [XXII] wherein R R R and X have the same meanings as mentionedabove, are sometimes obtained as intermediates, from which thephenylhydrazone derivatives represented by the formula [V] are preparedby heating.

In carrying out the process of the present invention, ester derivativesof B-keto acid represented by the formula [VII] may be allowed to reactwith the benzene diazonium salt represented by the formula [VIII] in thepresence of a base, for example, such as sodium hydroxide, potassiumhydroxide, sodium methylate and sodium ethylate, in an appropriatesolvent, for example, water, methanol and ethanol, whereby the reactionreadily proceeds. Because of unstability of the benzene diazonium salt,the reaction is preferably carried out below 10 C.

Thus, for example, the invention includes phenylhydrazone derivativessuch as methyl o-chlorophenylpyruvate p-chlorophenylhydrazone,

methyl o-fluorophenylpyruvate p-chlorophenylhydrazone,

ethyl o-fluorophenylpyruvate p-chlorophenylhydrazone,

tertiary butyl o-fiuorophenylpyruvate p-chlorophenylhydrazone and ethylo-chlorophenylpyruvate p-chlorophenylhydrazone.

At the second step, novel indole-Z-carboxylic acid derivativesrepresented by the formula [VI] wherein R R R and X respectively havethe same meanings as defined above, are readily obtained by treatingthese phenylhydrazone derivatives [V] in a solvent or solvent mixture.As solvents, there may be employed any solvent which is inert to thesystem as represented lower alkanols such as methanol, ethanol,isopropanol and tertiary butanol, aromatic solvents such as benzene,toluene, xylene, organic acids such as formic acid and acetic acid orother organic solvent such as acetone, chloroform and cyclohexane. Thereaction is preferably carried out in the presence of an acid; mineralacids such as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid and polyphosphoric acid, organic acid such as formicacid and acetic acid or other acidic reagents, including Lewis acidssuch as zinc chloride, iron chloride, aluminum chloride and boronfluoride. The reaction is generally eifected at elevated temperature.

Thus, for example, the invention includes indole-2-carboxylic acidderivatives such as,

3-(o-chlorophenyl)-5-chloro-indole-2-carboxylic acid,3-(o-fluorophenyl)-5-chloro-indole-Z-carboxylic acid,3-(o-bromophenyl)-S-chloro-indole-2-carboxylic acid, 3- m-chlorophenyl-5-chloro-indole-2-carboxylic acid, 3- (p-chlorophenyl-S-chloro-indole-2-carboxylic acid,

methyl 3-(o-fiuorophenyl)-5-chloro-indole-2-carboxyl- Still further, thenovel indole-Z-carboxylic acid derivatives represented by the formula[VI] are readily obtained by reacting the ketone derivatives representedby the formula [III] with the phenylhydrazine derivative represented bythe formula [IV] or its salt. The reaction mentioned above can hecarried out in a solvent, for example, an alkanol such as methanol,ethanol, isopropanol and tertiary butanol, aromatic hydrocarbon such asbenzene, toluene, xylene, and the like organic acid such as formic acidand acetic acid, and the like, or an other inert organic solvent such asacetone, chloroform, cyclohexane, and the like, preferably in thepresence of an acid catalyst, for example, mineral acid such as hydrogenchloride, hydrogen bromide, sulfuric acid, phosphoric acid,polyphosphoric acid, and the like, organic acid such as formic acid andacetic acid, Lewis acid such as zinc chloride, iron chloride, aluminumchloride, boron fluoride, and the like, or cation exchange resin. When asalt of the phenylhydrazine derivative [IV] is used as a startingmaterial, the reaction proceeds even in the absence of theabove-mentioned acid catalyst to give the objective indole derivatives[VI]. As salts of the phenylhydrazine derivatives [IV], following saltsare useful: for example, inorganic acid salt such as hydrochloride,hydrobromide and sulfate or organic acid salt such as acetate andoxalate.

The reaction usually proceeds at room temperature, but, if desired, thereaction may be controlled by heating or cooling, though the heating andcooling are not always necessary.

. Thus, for example, the invention includes indole derivatives such as,

3-(o-chlorophenyl)-5-chloro-indole-Z-carboxylic acid,

3-(o-bromophenyl)-5-chloro-indole-Z-carboxylic acid,

3-(o-fiuorophenyl)-5-chloro-indole-2-carbxoylic acid,

B-(m-chlorophenyl)--chloro-indole-Z-carboxylic acid,

3-(p-chlorophenyl)-5-chloro-indole-Z-carboxylic acid,

1-cyclopropylmethyl-3-(o-fiuorophenyl)-indole-2- carboxylic acid,

ethyl l-cyclopropylmethyl-3-(o-fluorophenyl)-indole-2- carboxylate,

l-cyclopropylmethyl-3-(o-fiuorophenyI-S-chloro-indole-2- carboxylicacid,

methyl l-cyclopropylmethyl-Zi-(o-fluorophenyl)-5-'chloro-indole-2-carboxylate,

ethyl1-cycIopropylmethy1-3-(o-fluorophenyl)-5-chloroindole-Z-carboxylate,

tertiary butyl 1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloro-indole-2-carboxylate,

benzyl1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloroindolev-Z-carboxylate,

ethyl l-cyclopropylmethyl-3' (o-fluorophenyl-5-bromoindole-Z-carboxylate,

methyl l-cyclopropylmethyl-Zi-(o-fiuorophenyl)-6 (or 4)-chloro-indole-2-carboxylate,

ethyl1-cyclopropylrnethyl-3-(o-chlorophenyl)-7-chloroindole-Z-carboxylate,

ethyll-cyclopropylmethyl-Ii-(o-chlorophenyl)-5-chloroindole-Z-carboxylate,

ethyll-cyclopropylmethyl-3-(o-bromophenyl)-5-chloroindole-Z-carboxylate,

ethyll-cyclopropylmethyl-3-(m-chlorophenyl)-5-chloroindole-Z-carboxylate,

ethyl1-cyclopropylmethyl-3-(p-chlorophenyl)-5-chloroindole-Z-carboxylate,

8 ethyll-cyclohutylmethyl-B-(o-fluorophenyl)-5-chloroindole-Z-carboxylate,ethyll-cyclophenylmethyld-(o-fluorophenyl)-5-chloroindole-Z-carboxylate,ethyl I-cyclohexylmethyl-3-(o-fluorophenyl)-5-chloro-.indole-2-carboxylate, r Y 1 methyl l-methyl-3- (o-fluorophenyl-5-chloro-indole-2- carboxylate, 1-ethyl-3- (o-fiuorophenyl-5-chloro-indo1e-2-carboxylic acid, 1-methyl-3- (o-chlorophenyl)-5-chloro-iridole-Z-carboxylic acid,

methyl 1-n-propyl-3- (o-fluorophenyl -5-chloroindole-2 carboxylate,1-methyl-3-(o-fluorophenyl)5-bromoindole-2-carboxylic acid,1-methyl-3-(o-chlorophenylindole)-2-carboxylic acid, methyl3-(o-fluoroph'enyl)-5-chloroindole-2-carboxylate,

and l-isobutyl-S-(o-fiuorophenyl)-5-chloro-indole-2- carboxylic acid.

Furthermore, novel indole-Z-carboxylic acid ester derivativesrepresented by the formula [IX] wherein R R and X have the same meaningsas described above, is obtained by treating ester derivative of fl-ketoacid represented by the formula [VII] with a benzene diazonium saltderivative represented by the general formula [VIII].

In carryling out this process, the ester derivatives of B-keto acidrepresented by the aforesaid formula [VII] may be allowed to react withthe benzene diazqnium salt represented by the aforesaid formula [VIII]in-the presence of a base, such as sodium hydroxide, potassiurnfhy--droxide, sodium methylate and sodium ethylate in an appropriate solvent,such as Water, methanol and ethanol, whereby the reaction readilyproceeds. Because of unstability of the benzene diazonium salt, it ispreferable to carry out the reaction below 10 C., more preferably below5" C. Thereafter, treatment of the reaction product with an acid causesformation of the indole-Z-carboxylic acid ester derivative representedby the aforesaid formula [IX]. However, an intermediate produced duringthis reaction is preferably once isolatedvand treated with an acid in anorganic solvent to yield very readily the aimed indole-2-carboxylic acidester 7 derivative [IX] in good yield. In this reaction, an acid, forexample, mineral acid such as hydrogen chloride, hydrogen bromide,sulfuric acid, phosphoric acid, polyphosphoric acid. and the like, orother Lewis acid such as zinc chloride, ferrous chloride, aluminumchloride, stannous chloride, boron fluoride and the like is suitable.

In this reaction, following solvents are most useful, for example,alkanols such as methanol, ethanol and isproppanol, aromatichydrocarbons such as benzene, toluene and xylene, organic acids such asformic acid and acetic acid, or common organic solvents such as acetone,chloroform and cyclohexane.

Thus, for example, the invention includes indole-2- carboxylic acidester derivatives such as methyl3-(o-fluorophenyl)-5-chloro-indole2-carboxylate, ethylS-(o-chlorophenyl)-S-chloro-indole-2-carboxylate, ethyl3-(o-fiuorophenyl)-5-chlorindole-2-carboxylate, ethyl3-(o-bromophenyl)-5-chlorosindole-2-carboxy1ate, ethyl3-(m-chlorophenyl)-5vchloro-indole-2-carhoxylate, ethyl 3-p-chlorophenyl) -5fchloro-indole-2-carboxylate, tertiary butyl3-(o-fluorophenyl)-6-chloro-indole-2-f carboxylate,

benzyl 3-(o-fluorophenyl)-5-chloro-indole-2-carboxylate,

ethyl 3-(o-fiuorophenyl)-6 (or 4)-chloro-indole-2- carboxylate and ethyl3-(o-fluorophenyl)-7-chloro-indole-2-carboxylate.

resented by the formula [XI] wherein R R and X each has the samemeanings as defined above, can be produced by converting an indole-2-carboxylic acid ester derivative represented by the formula N COORawherein R R R and X have the same meanings as defined above, to itscorresponding acid.

The indole-Z-carboxylic acid ester derivative represented by theaforesaid formula [X] is treated in water and/or alcohols such asmethanol and ethanol, preferably in the presence of a hydrolyzing agent,to readily give the indole-Z-carboxylic acid derivative represented bythe formula [XI].

As a hydrolyzing agent, following compounds are useful; for example,mineral acid such as hydrochloric acid and sulfuric acid, alkali metalsuch as sodium, potassium and lithium, alkali metal hydroxide such assodium hydroxide and potassium hydroxide, alkali metal carbonate such assodium carbonate and potassium carbonate, alkaline earth metal hydroxidesuch as barium hydroxide, and calcium hydroxide, and ammonium compoundsuch as ammonium hydroxide or the like. Alkali metal hydroxide oralkaline earth metal hydroxide is preferred. The reaction can be carriedout even at room temperature, preferably at an elevated temperature.

Furthermore, the indole-2-carboxylic acid ester derivative [X] can alsobe hydrolyzed by treating the same in an organic acid such as aceticacid and propionic acid in the presence of a mineral acid.

Alternatively, when R is a tertiary butyl group, the indole-Z-carboxylicacid ester derivative [X] can also be converted to the objectivecarboxylic acid [XI] by heating the same together with a mineral acid ortoluenesulfonic acid. When R is a benzyl group, the benzyl group canalso be removed by hydrogenolysis. The objective substance can beobtained as a metal salt or ammonium salt.

Thus, for example, the invention includes following indole-Z-carboxylicacid derivatives such as 3-(o-chlorophenyl)-S-chloro-indole-2-carboxylicacid, 3-(o-fluorophenyl)-5-chloro-indole-2 carboxylic acid, 3-(m-chlorophenyl)-5-chloro-indole-2-carboxylic acid,3-(p-chlorophenyl)-5-chloro-indole-2-carboxylic acid, 3-phenyl-6 (or4)-chloro-indole-2-carboxylic acid,3-pl1enyl-7-chloro-indole-2-carboxylic acid,1-methyl-3-(o-chlorophenyl)-5-chloro-indole-2-carboxylic acid,1-methyl-3-(o-bromophenyl)-5-chloro-indole-2-carboxylic acid,

1-methyl-3-(o fluorophenyl)-5-chl0ro-indole-2-carboxylic acid,

1-ethyl-3-(o-fluorophenyl)-5-chloro-indole-Z-carboxylic acid,

1-cyclopropylmethyl-3- (o-chlorophenyl) -S -chloroindole-2carboxylicacid,

1-cyclopropylmethyl-3- (o-fluorophenyl -5 -bromo-indole- 2-carboxylicacid,

1-cyclopropylmethyl-3-(o-fluorophenyl)-6 (or4)-chloroindole-2-carboxylic acid,

l-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloroindole-Z-carboxylic acid,

1-cyclopropylmethyl-3-(o-fluorophenyl)-indole-2-carboxylic acid,

1-cyclobutylmethyl-3- (o-fluorophenyl) -5-chloro-indole- Z-carboxylicacid,

1-cyc1opropydmethyl-3- (m-chlorophenyl -5-chloroindole-2-carboxylicacid,

1-cycl0propylmethyl-3-(p-chlorophenyl)-5-chloroindole-Z-carboxylic acid,

1-cyclobutylmethyl-3- (o-fluorophenyl -5-bromo-indole- 2-carb0xylicacid,

1-cyclopentylmethyl-3- (o-fluorophenyl -5 -chloro-indole- 2-carboxylicacid and l-cyclohexylmethyl-3 (o-fluorophenyl) -5-chloro-indole-2-carboxylic acid.

Novel N-alkylindole-2-carboxylic acid derivatives represented by thegeneral formula [X] I la [X wherein R R and X have the same meanings asdefined above and R represents a lower alkyl having 1-3 carbon atoms ora cycloalkylmethyl having 4-7 carbon atoms, is obtained by reacting anindole-2-carboxylic acid derivative represented by the formula [VI'] R,[VI'] wherein R R and X have the same meanings as defined above, withalkylating agents. The alkylation is carried out by treating anindole-2-carboxylic acid derivative represented by the formula [VI'] inthe presence of an alkaline condensing agent, if necessary, or with analkaline condensing agent to form an alkaline metal salt thereof, andthen treating with an alkylating agent. As the alkaline condensingagent, following compounds are useful, for example, alkali metal,alkaline earth metal, alkali metal hydroxide, alkaline earth metahydride, alkali metal hydroxide, alkaline earth metal hydroxide, alkalimetal amide and alkaline earth metal amide.

Alkylation of an indole-2-carboxylic acid ester derivative representedby the formula [VI'] is carried out by contacting it with followingcompounds, for example, alkyl halide such as methyl iodide, ethylbromide, ethyl iodide, butyl bromide and cyclopropylmethyl. bromide,alkyl sulfate such as dimethyl sulfate and diethyl sulfate, and suchalkyl aromatic sulfonate as methyl paratoluenesulfonate andcyclopropylmethyl paratoluenesulfonate.

Thus, for example, the invention includes indole-Z-carboxylic acidderivatives such as,

methyl l-methyl-3- (o-chlorophenyl) -5-chloro-indole- Z-carboxylate,

methyl- 1-methyl-3- (o-fiuorophenyl) -5-chloro-indole- 2-carboxy1ate,

ethyl 1-methyl-3-(o-bromophenyl)-S-chloro-indole- 2-carboxylate,

ethyl 1-methyl-3-(o-chlorophenyl)-5-chloro-indole- Z-carboxylate, v Y 1y ethyl l-methyl-3-(m-chlorophenyl)-5-chloro-indole- Z-carboxylate, Y v

ethyl 1-methyl-3-(p-chlorophenyl)-5-chloro indole- 2-carboxylate, 1

ethyl l-methyl-3-(o-fluorophenyl)-5-chloro-indo1e- Z-carboxylate,

benzyl l-methyl-3-(o-fluorophenyl)-5-chloro-indole- 2-carboxylate,

ethyl 1-ethyl-3-(o-fluorophenyl)-5-chloro-indole- Z-carboxylate, V

ethyl 1-propyl-3-(o-fluorophenyl)-5-ch1oro-indole- 2-carboxylate,

ethyl 1-methyl-3-(o-fluorophenyl)-6 (or 4)-chloro-indole- Z-carboxylate,

methyl 1-methyl-3-(o-chlorophenyl-7-chloro-indole- 2-carboxylate,

ethyl 1-methyl-3-(o-chlorophenyl)-7-ch1oro-indole- 2-carboxylate,

ethyl 1-methyl-S-(o-chlorophenyl)-5-bromo-indole- 2-carboxylate,

ethyl 1-cyclopropylmethyl-3-(o-chlorophenyD-indole- Z-carboxylate,

methyl l-cyclopropylmethyl -3-(o-fiuorophenyl)-5-chloro-indole-Z-carboxylate,

ethyl l-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloro-indole-Z-carboxylate,

benzyl l-cyclopropylmethyl-3-(fluorophenyl)-5-chloro-indole-2-carboxylate,

ethyl 1-cyclopropylmethy1-3-(o-fluorophenyl)-5-bromo-indole-Z-carboxylate,

ethyl 1-cyclopropylmethyl-3-(m-chlorophenyl)-5-chloro-indole-2-carboxylate,

ethyl 1-cyclopropylmethyl-3-(p-chlorophenyl -5-chloro-indole-Z-carboxylate,

ethyl1-cyclobutylmethyl-3-(o-fluorophenyl)-5-chloroindole-2-carboxylate,

ethyl 1-cyc1opentylmethyl-3-(o-fluorophenyl)-5-chloro-indole-2-carboxylate,

ethyl l-cyclohexylmethyl-Zi-(o-fluorophenyl)-5-chloro-indole-Z-carboxylate,

l-methyl-3- (o-chlorophenyl)-indole-2-carboxylic acid,

1-methyl-3- (o-fluorophenyl)-indole-2-carboxylic acid,

1-methyl-3-(o-chlorophenyl)-5-chloro-indole-Z-carboxylic acid and1-methyl-3-(o-fluorophenyl)-5-chloro-indole-Z-carboxylic acid.

Further, N alkylindole 2 carboxylic acid derivatives [X] in which R isan alkyl or benzyl group is converted to indole-Z-carboxylic acidderivative [XI'].

o o l? C H R [XI] wherein R,, R, and X have the same meanings as definedabove.

At the third step, a novel indole-Z-carboxylic acid derivativerepresented by the formula [XII] N -CONHY In this reaction, followingacid halides can be used, for example, acid chloride and acid bromide.Following esters can be used, for example, tertiary butyl ester, benzylester or paranitrophenyl ester. Following acid anhydrides can be used,for example, a mixed anhydridewhich includes mixed anhydrides describedin Organic Reactions, vol. 12, p. 157 (1962), for example, loweraliphatic anhydride, particularly that of acetic acid or an anhydride ofcarboxylic acid half esters obtained by reacting an acid represented bythe formula [XI] with methyl chloroformate, ethyl chloroformate,isobutyl chloroformate, alkyl chloroformate, benzyl chloroformate orchloroformic' acid paranitrophenyl ester. i

In carrying out this process, the indole-Z-carboxylic acid derivativerepresented by the aforesaid formula [XI] or its reactive derivativesuch as acid halide, ester or acid anhydride is allowed to react withammonia.

In the present reaction, the presence of a solvent is preferable. In thereaction following solvents can be used, for example, alcohols such asmethanol, ethanol and organic solvents such as acetone, benzene,toluene, xylene, chlorobenzene and chloroform.

In the present reaction, ammonia can be used by introducing gaseousammonia to a reaction mixture or adding alcoholic ammonia (such asmethanolic ammonia, ethanolic ammonia) or aqueous ammonia to a reactionmixture.

Because the reaction usually proceeds at room temperature, heating orcooling is not always necessary. However, ther eaction may be controlledby heating or cooling, if desired.

Furthermore, when the indole-Z-carboxylic acid derivative represented bythe formula [XI] or its reactive de-' rivative is heated withhydroxylamine or its salt inan appropriate solvent, for example, inalcohol, the corresponding hydroxamic acid derivative is obtained.

Thus, for example, the invention includes indole Z- carboxylic acidderivatives [XII] such as 1-cyc1opropylrnethyl-3-(o-chlorophenyl)5-chloro indole-2-carboxamide, 1-cyclopropylmethyl-3(o-fiuorophenyl)-5-bromoindole-2-carboxamide, 1-cyclopropylmethyl-3-(o-fluorophenyl -5-ch1oroindole-Z-carboxamide,1-cyclopropylmethyl-3-(o-fluorophenyl)-6 (or4)-chloroindole-Z-carboxamide,1-cyc1opropylmcthyl-3-(o-fluorophenyl)-5-chloroindolc-Z-hydroxamic acid,l-cyclopropylmethy1-3-(o-fiuorophenyl)-7-chloroindole-Z-carboxamide,l-cyclobutylmethyl-S- (o-fluorophenyl) -5-chloroindole-2-carboxamide,l-cyclopentylmethyl-3-(o-fluorophenyl)-5-mcthyl indole-Z-carboxamide,1-cyclohexylmethyl-3- (o-fiuorophenyl -5-chloro-' indole-2-carboxamide,I 1-cyclohexylmethyl-3-(o fluorophenyl) 5-chloroindole-2-carboxamide,3-(o-chlorophenyl)-5 chloro-indole-2-carboxamide, 3-(o-bromophenyl)-5-chloro-indole-2-carboxamide, 3 o-fiuorophenyl -5-chloro-indole-2-carboxamide, 3 p-chlorophenyl -5 chloro-indole 2carboxamide, 3 (m-chlorophenyl) -5-chloro-indole-2-carboxamide,3-(o-fiuorophenyl) S-brorno-indole-Z-carboxamide, 3- (o-fiuorophenyl)-5fluoro-indole-2-carboxarnide, 3-(o-fiuorophenyl)-6 (or4)-chloro-indole-2-carboxamide,3-(o-fluorophenyl)-7-chloro-indole-Z-carboxamide,1-methyl-3-(o-fluorophenyl)-5-chloro-indole2f hydroxamic acid,l-methyl-3-(o-chlorophenyl)-5-chloro-indole-2- carboxarnide,1-methy1-3-(o-fluorophenyl) 5-bromo-indole-2- carboxarnide,1-methyl-3-(o-fiuorophenyl)-5-fluoro-indole-2- carboxamide and l-ethyl-3- o-fluorophenyl) -5-chloro-ihdole-Z-carboxamide.

'13 An indole-Z-carboxylic halide represented by the formula [XIII]wherein R R and X respectively have the same meanings as defined aboveand X represents a halogen atom, is obtained by reacting theindole-Z-carboxylic acid derivative [XI] with a halogenating agent.

In carrying out this process, the indole-2-carboxylic acid derivativerepresented by the aforesaid formula [XI] is treated together with ahalogenating agent in the absence of a solvent or in an inert solvent,such as benzene, toluene, ether, chloroform, methylene chloride andcarbon tetrachloride. As the halogenating agent, following compounds areuseful; for example, thionyl chloride, phosphorous trichloride,phosphorous tribromide, phosphorous pentachloride, phosphorousoxychloride and phosgene. In this case, the reaction rate can also beaccelerated by adding a basic substance such as pyridine anddimethylformamide. Furthermore, in this process, a free carboxylic acidcan be used as a starting material, but the metal salt, such as sodiumsalt, may also be used.

After removing the solvent and excess of reacting agents, the reactionproduct is obtained, if necessary, by treatment such as extraction withan inert solvent to give the objective product. In this case, isolationor further purification of this product is not always easy. However, inleading the indole-Z-carboxylic halide, for example, toindole-Z-carboxylic acid amide, isolation or purification is not alwaysnecessary and crude products or a reaction mixture will be used as it isfor carrying out the reaction.

Thus, for example, the invention includes indole-2- carboxylic acidhalide derivatives such as 3-(o-chlorophenyl)-indole-2-carboxylicchloride, 3-(o-fluorophenyl)-indole-2-carboxylic chloride,3-(o-chlorophenyl)-5-chloro-indole-2-carboxylic chloride,3-(o-fiuorophenyl)-S-chloro-indole-2-carboxylic chloride,3-(p-chlorophenyl)5-chloro-indole-2-carboxylic chloride,3-(o-fiuorophenyl)-5-chloro-indole-2-carboxylic bromide,3-(o-fluorophenyl)-5-bromo-indole-2-carboxylic chloride,3-(o-fiuorophenyl)-S-fluoro-indole-2-carboxylic chloride,3-(o-fluorophenyl)-S-chloro-indole-Z-carboxylic bromide, 3-(o-fiuorophenyl -indole-2-carboxylic bromide, 3-(o-fiuorophenyl)-6 (or4)-chloro-indole-2-carboxylic chloride,3-(o-fiuorophenyl)-7-chloro-indole-2-carboxylic chloride,1-methyl-3-(o-chlorophenyl)-5-chloro-indole-2-carboxylic chloride,1-rnethyl-3-(o-fluorophenyl)-5-chloro-indole-2-carboxylic chloride,1-ethyl-3 (o-fiuorophenyl) -5-chloro-indole-2-earboxylic chloride,1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloro-indole- 2-carboxylicchloride, 1-cyclobutylmethyl-3 o-fiuorophenyl -5-chloro-indole-2-carboxylic chloride, 1-cyclopentylmethyl-3- (o-fiuorophenyl -5-chloro-indole- 2-carboxylic chloride and 1-cyclohexylmethyl-3(o-fluorophenyl -5-chloro-indole- Z-carboxylic chloride.

Furthermore, an indole derivative represented by the formula [XV]wherein R R and X have the same meanings as defined above, an beobtained by alkylating an amide derivative represented by the generalformula [XIV] wherein R and X have the same meaning as identified above.

In practising this process, the indole derivatives represented by theaforesaid formula [XIV] give their alkaline metal salt by treating thesame in the presence of an alkaline condensing agent, and then theresultant alkaline metal salt may be allowed to react with an alkylatingagent or cycloalkylmethylating agent. As the alkaline condensing agent,following compounds are useful: for example, alkali metal, alkalineearth metal, alkali metal hydride, alkaline earth metal hydride, alkalimetal hydroxide, alkali earth metal hydroxide, alkali metal amide andalkaline earth metal amide.

Thus, for example, the invention includes compounds such as 1-methyl-3-(o-chlorophenyl) -5-chloro-indole-2-carb oxamide,

1-methyl-3 (o-fiuorophenyl -5-chloro-indole-Z-carboxamide,

1-methyl-3- (p-chlorophenyl) -5 -chloro-indole-2-carb oxamide,

1-methyl-3- (o-fluorophenyl) -5-bromo-indole-Z-carboxamide,

1-ethyl-3- (o-fluorophenyl) -indole-2-carboxamide,

1-cyclopropylmethyl-3- o-fiuoropheny) -indole-2-carboxamide and1-cyclopropylmethyl-3- o-fluorophenyl) -5-chloroindole-2-carboxamide.

At the final step for producing the 2-aminomethyl-indole derivatives[II], a novel Z-aminomethylindole derivative represented by theaforesaid formula [II] I [II] wherein [R R and X respectively have thesame meanings as defined above, is obtained by converting an indole-2-carboxylic acid derivative represented by the formula l [X I] whereinR R and X respectively have the same meanings as defined above and Wrepresents an oxygen or sulfur atom, and Y is hydrogen atom or hydroxylgroup.

In the formula [XVI], when W is a sulfur atom (i.e. indole-Z-carboxylicthioamide derivative), the compound [XVI] is produced, for example, byreacting indole-2- carboxylic amide derivative [XII] with phosphoruspentasulfide.

In practising this process, the reduction of the indole-2- carboxylicderivative represented by the formula [XVI] is carried out according tousual method of reduction, such as electrolytic reduction, reduction byalkali metal in alcohols, catalytic reduction in the presence of acatalyst such as platinum, palladium, nickel catalyst and the like, orreduction with use of metal hydride complex com- 1 pound. Particularlypreferable reduction agents are a metal hydride complex, for example,lithium-aluminum hydride.

The aminomethyl compound [II] obtained by the above process can beconverted ,to the corresponding salt by treating the same with an acid,for example, mineral acid such as hydrochloric acid, hydrobromic acid,sulfuric acid and phosphoric acid;

Thus, for example, the invention includes Z-aminomethyl-indolederivatives such as 2-aminomethyl-3-(o-chlorophenyl)-indole,2-arninornethy1-3 (o-fiuorophenyl) -indole, 2-amino'methyl-3=(ochlorophenyl) 5-chloro indole, 1 2-aminomethyl-3- (o-fluorophenyl)-5bromo-indole, Z-aminomethyl-3-(oafluorophenyl -6 (or4)-chloro-indole, 2-aminomethyl-3-(o-fluorophenyl)-7-chloro-indole,1-methyl-2-aminomethyl-3- (o-fluorophenyl) -indole,l-methyl-Z-aminomethyl-S-(o-chlorophenyl) -indole,l-methyl-2-aminomethyl-3-( o-chlorophenyl) -5-chloroindole,1-ethyl-2-arninomethyl-3-(o-fluorophenyl) -5-chloroindole,1-methyl-2-aminomethyl-3-(o-fluorophenyl)-5-bromoindole,1-methyl-2-aminomethyl-3-(o-fiuorophenyl) -5-chloroindole,l-cyclopropylmethyl-2-aminomethyl-3- (o-fiuorophenyl) indole,1-cyclopropylmethyl-2-a-minomethyl-3- (o-fluorophenyl)- 5chloro-indole,1-cyclopropylmethyl-2aminomethyl-3- (o-fiuorophenyl) 5 -bromo-indole,1-cyclopropylmethyl-Z-aminomethyl-3-(o-chlorophenyl)- 6 (or 4)-chloro-indole, l-cyclopropylmethyl-Z-aminomethyl-3-(o-bromophenyl) 5-ch1oro-indole, 1-cyclobutylmethyl-2-aminomethyl-3- (o-fiuorophenylS-chloro-indole, I 1-cyclopropylmethyl-Z-aminomethyl-3-(o-tfluorophenyl) S-bromo-indole, 1-cyclopropylmethyl-2-aminomethyl-3-(o-fiuorophenyl) 5fluoro-indole and their hydrochlorides, hydrobromides,sulfates, nitrates and phosphates.

Alternatively, the Z-aminomethyl indoles represented by the formula [II]can also be prepared in good yield by heating the corresponding amidederivatives [XVIII] to the corresponding carbonitrile derivatives [XIX]and reducing the said carbonitrile derivatives.

B1 [III \N 0N i p wherein R 'R and Xrespectively have the same meaningsas defined above. More particularly, according to the dehydration of anindole-Z-carboxam-ide derivative represented by the formula [XVIII], anindole-Z-carbonitrile derivative [XIX] is obtained.

In practising this process, an indole-2-carboxamide derivativerepresented by the aforesaid formula [XVIII] is heated, preferably inthe presence of a dehydrating agent to give an indole-Z-carbonitrilederivative [XIX]. As the dehydrating agent, following compounds areuseful; for example, phosphorous halide such as phosphorous oxychloride,phosphorous trichloride and phosphorous pentachloride or acid chloridesuch as p-toluenesulfonyl chloride, methylsulfonyl chloride, acetylchloride, thionyl chloride, benzoyl chloride and carbobenzoxy chloridein the presence or absence of an inert solvent.

Thus, for example, the invention includes indole-Z-carbonitrilederivatives such as 3- (o-c'hlorophenyl -indole-2-carbonitrile,

3-(ofluorophenyl) -indole-2-carbonitrile,

3- (o-chlorophenyl) -5 ch1oro-indole-2-carbonitrile,

3- (o-fiuorophenyl -5-chloro-indole-2- carbonitrile,

3- (o-bromop henyl-S-chloro-indole-Z-carb onitrile,

3- (pchloro-phenyl) -5-chloro-indole-2-carbonitrile,

3- o-fluorophenyl) -5-bromo-indole-Z-carbonitrile,

3- (o-flu orophenyl) -5 -fluoro-indole-2-carbonitrile,

3- (o-fluorophenyl) -6 (or 4) -chloro-indole-2-carb onitrile,

3 o-llluorophenyl) 7-chloro-indole-2- carbonitrile,

1 -methyl- 3- (o-fluorophenyl) -5-chloro-indole-2-carbonitrile,

l-methyl-3 o-chlorophenyl) -5-chloro-indole-2-carbonitrile,

1-cthyl-3- ofluorophenyl) -5-chloro-indole-2-carbonitrile,

l-cyclopropyl-methyl-Iao-fluorophenyl) -indole-2-carbonitrile,

1-cyclopropylmethyl-3 (o-fluorophenyl) -5chloro-indole-Z-carbonitrile,

l-cyclobutylmethyl- 3- o-fiuorophenyl) -5- chloro-indole- 2-carbonitrile,

1-cyclopentylmethyl-3- (o-fluorophenyl) -5-chloro-indole- Z-carbonitrileand 1-cyclohexylmethyl-3- (o-fluorophenyl) -S-chloro-indole- Z-carbonitrile.

Subsequently, by reducing an indole-Z-carbonitrile derivativerepresented by the formula [XIX], a Z-aminomethyl indole derivativerepresented by the aforesaid formula ['II] can readily be obtained. Moreparticularly, reduction of the indole-2-carbonitrile derivativerepresented by the aforesaid general formula [XIX] may be carried out bya usual method, for example, electrolytic reduction, reduction by alkalimetal in alcohol, catalytic reduction. by palladium, nickel or platinum,reduction by chromium acetate-alkali, or reduction by metal hydridecomplex. Particularly, reduction by metal hydride complex, for example,aluminum-lithium hydride, boron hydride, a mixed hydride, iscommercially useful from points of simplicity and selectivity.

The Z-aminomethyl-indole derivative [II] can be converted to thecorresponding salt by treating with, for example, a mineral acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid ororganic acid such as acetic acid.

Thus, for example, the invention includes Z-aminomethyl-indolederivatives such as 2-aminomethyl-3 (o-fiuorophenyl) -indole,

2-aminome thyl-3- (o-chlorophenyl )-5-chloro-indole,

2-aminomethyl-3- (o-fluorophenyl -5'-chloro-indole,

2aminomethyl-3- (o-fluorophenyl) -5-bromo-indole,

2-aminomethyl-3 o-fluorophenyl) -5- fiuoro-indole,

2-aminomethyl-3- (o-fluorophenyl) -6 (or 4) -chloro indole,

2-aminomethyl-3 (o-fluorophenyl) -7-chloro-indole,

l-methyl-2-aminomethyl-3- (o-chlorophenyl) -5-chloroindole,

1-methyl-2-aminomethyl-3- (o-fiuorophenyl -5-chloroindole,

1-ethyl-2-aminomethyl-3-(o-fiuorophenyl -5 -ch1oroin dole,

1-cyclopropylmethyl-2-aminomethyl-3 (o-fluoro-ph enyl) ind ole,

1-cyclopropylmethyl-Z-aminomethyl-3- o-fluorophenyl) S-chloro-indole,

1-cyclobutylmethyl-2-aminomethyl-3- (o-fluorophenyl) S-chloro-indole,

. 17 1-cyclopentylmethyl-2-aminomethyl-3- (ofluorophenyl) -chloro-indole, 4 1-cyclohexylmethyl-2-aminomethyl-3- (o fluorophenyl)S-chloro-indole and their hydrochlorides, hydrobromides, sulfates,phosphates andacetates. 5

Otherwise 2-aminomethylindole derivatives represented by the formula, r

[XVII] wherein-R ,.R and X have the same meanings as defined above, areproduced from novel N-alkyl-indole-Z-carbonitrile derivativesrepresented by the formula [XXI] wherein R and X have the same meaningas defined above. Y v

In-:practisingthe present process, the indole-Z-carbonitrile derivativerepresented by the aforesaid formula [XX] is treated with an alkylatingagent, if necessary, in the presence of an alkaline condensing agent, orafter formation ofalkali metal salts by treating with an alkalinecondensing agent..As the alkylating agent, following compounds areuseful:-' for example, alkyl halide such as methyl iodide, ethyl bromideand butyl bromide cyclopropylmethylbromide, alkyl-s'ulfuric ester suchas dimethyl sulfate, diethyl sulfate or aromatic sulfonic alkylestersuch as methyl paratoluenesulfonate and cyclopropyhnethyl paratoluenesulfonate; As the alkaline condensing agent, following compounds areuseful: for example, alkali metal, alkaline earth metal, alkali metalhydride, alkaline earth metal hydride, alkali metal hydroxide, alkalineearth metal hydroxide, alkali metal amide and alkaline earth metalamide.

Thus, for example, the invention includes N}alkylindole 2-carbonitrilederivatives such as l-methyl-3-(o-fluorophenyl)-indole:2-carbonitrile,

nitrile, I 1-methyl-3-(o chlorophenyl)-5-chloro-ch1oroindole2-carbonitrile, 1-methyl-3-(o-fluorophenyl) -'6- (or 4)-indole-2-carbonitrile, 1-methyl-3- (o-fluorophenyl)-7-chloro-indole-2-carbo- ,nitrile, v1-methyl3r(o-fluorophenyl)-S-bromo-indole-iZ-carbonitrile, I1-ethyl-3-(o-fluorophenyl)-5-chloro-indole-Z-carbonitrile and H1-propyl-3-(o-fluorophenyl)-5-chloro-indole-2-carbonitrile.

Subsequently, the above-mentioned indole-Z-carbonitrile derivatives[XXI] are reduced according to the aforesaid process,2-aminomethyl-3-phenyl-indole derivatives represented by the formula[XVII] CHzNH: R. [XVII] wherein R R and X each has the same meaning asdefined above are obtained.

If the 2 aminomethyl 3 phenyl-indole derivatives [XVII] are treated withan oxidizing agent as mentioned before to give the benzodiazepinederivatives represented by the formula [I'], which is the objectiveproduct of the present invention,

R: i ll Rs 0 wherein R R and X have the same meanings as defined above.

The following examples also are illustrative of the meth ods by whichthe products of this invention can be prepared and are not to beconsidered as limiting the invention to the particular proceduralconditions employed or to the particular compounds prepared thereby.

EXAMPLE 1 A mixture of 20 g. of o-chlorophenylpyruvic acid, 300 ml. ofethanol and 14 g. of p-chlorophenyl-hydrazine was heated for 30 min.After the reaction is completed, the solvent was removed under reducedpressure to give pchlorophenyl hydrazone of o-chlorophenylpyrvic acidalmost quantitatively. Melting point 124-125 C. Infrared absorptionspectrum,

ggg 3260, 1700, 1600 cm. EXAMPLE 2 According to the similar procedure tothat of Example 1, there was obtained a phenylpyruvic acidphenylhydrazone from phenylhydrazine and phenylpyruvic acid.

The following phenylhydrazone derivatives were obtained by the procedureof Example 1.

EXAMPLE 3 To. an ice-cold solution of 99.4 g. of ethylo-fluorobenzylacetoacetate in 420 ml. of ethanol was added-dropwise ml.of 50% aqueous potassium hydroxide solution N -methyl-p-chlorophenyloncooling, and then 80 ml. of ice-water was added to the mixture. To thismixture was added dropwise, diazonium salt solution prepared from 53.3g. of p-chloroaniline, 180 m1. of cone. hydrochloric acid, 28.8 g. ofsodium nitrite and 275 ml. of water, below 5 C. After addition, thereaction mixture was stirred below 5 C. The separated oily productsolidified gradually, and the solid substance was then collected byfiltration, washed with water and dried to give 128.4 g. (92.2%) ofethyl a(o-fluorobenzyl)-a-(p-chlorophenyl-azo) acetoacetate, m.p. 55 60C. Recrystallization from ethanol was repeated for an analytical sample,m.p. 79 -80 C. Infrared absorption spectrum,

1m; 1750, 1715, 1600, 1580, 1195 emf- Elementary analysis (for;3CnHlsClFNQOS),

percen C H N 01 Calculated 61. 54 4. 86 7. 56 9. 58 Found 61. 20 4. 537. 31 9. 56

ethyl calcioacetoacetate, m.p. 220-221 C.

A mixture of 87 g. of o-fluorobenzyl bromide, 137 g. of ethylcalcioacetoacetate and 300 ml. of dimethylformamide was heated at 75 C.for 6 hours. After completion of the reaction, the solvent was removedby distillation under reduced pressure, and 150 ml. of ethanolichydrogen chloride was added to the residue. The mixture was stirred atroom temperature to decompose the unreacted salt. The solvent wasremoved by distillation under reduced pressure, and 200 ml. of water wasadded to the residue. The separated yellow oil product was extractedwith ether, and the organic layer was washed with water, dried oversodium sulfate and concentrated, and the residue was distilled underreduced pressure to give 99.4 g. (90.8%) of ethyl o-fluorobenzylacetoacetate, hp. 164- 167 C./23 mm. Hg. Infrared absorption spectrum.

1740, 1720, 1590, 1496 elm- Elementary analysis (for CnHrsFOI), PercentCalculated. 65. 55 6.30 Found. 65. 40 6. 04

EXAMPLE 4 A mixture of 26.3 g. of p-chloroaniline, 69 g. of cone.hydrochloric acid and 50 ml. of water was heated into a solution andthen cooled to 2 C. To the mixture was added dropwise a solution of 14.6g. of sodium nitrite in water at -5 C. with stirring, and the resultantmixture was stirred at the same temperature for an additional 15 min. Tothe mixture was added portionwise 27.2 g. of.

sodium acetate at 0-5 C. The mixture was added dropwise to a chilledmixture of 47.6 g. of ethyl e-(o-fluorobenzyl) acetoacetate, 200 ml. ofmethanol and 33.7 g. of anhydrous potassium acetate below 5 C. withstirring. The reaction mixture was stirred for 2 hours below 5' C. Theprecipitate formed was collected by filtration, washed with water anddried in vacuo to yield 68.3 g. (90.7%) of ethyla(o-fluorobenzyl)-a-(p-chlorophenylazo) acetoacetate, m.p. 74--77 C. Theethyl a-(o-fluorobenzyl) acetoacetate used as a starting material inthis example was obtained as follows: To a suspension of 13.6 g. ofsodium ethoxide in 100 ml. of dry toluene, was added dropwise 31.2 g. ofethyl acetoacetate. To the mixture was added dropwise 54.6 g. ofo-fluo'robenzylbromide and the mixture was refluxed for 8 hours. Thereaction mixture was cooled and filtered. The filtrate was concentratedand the residue was distilled under reduced pressure to give 36.7 g. ofethyl ot(o-fiuorobcnzyl) acetoacetate, b.p. 159-161 C./ 19 mm. Hg.

The following compounds were similarly prepared:

Ethyl u-(o-chlorobenzyD-e-(phenyl-azo) acetoacetate,

methyl a-(o-fluorobenzyD-a-(p-chloro-phenyl-azo)- acetoacetate,

tert.Butyl a-(o-fluorobenzyl)-u-(p-chloro-phenyl-azo) acetoacetate,

ethyl a-(o-fiuorobenzyn-bt- (p-bromo-phenyl-azo) acetoacetate,

ethyl u-(o-fluorobenzylya-(m-chloro-phenyl-azo) acetoacetate and ethyla-(o-chlorobenzyl)-u-(p-chloro-phenyl-azo) acetoacetate.

EXAMPLE 5 A mixture of 47.1 g. of p-chloroaniline, 118 ml. of cone.hydrochloric acid andml. of water was heated and then cooled below 0 C.To the mixture was added dropwise, a solution of 25.6 g. of sodiumnitrite in 5 8 ml. of water below 5 C. with stirring. After addition, 43g. of sodium acetate was addedto the mixture. The resulting mixture wasadded dropwise to a chilled mixture of 93.6 g. of ethyla-(o-chlorobenzyl) acetoacetate, 360 ml. of ethanol and 72 g. ofanhydrous potassium acetate below 5 C., and the reaction mixture wasstirred overnight below 5 C. To the reaction mixture was added ml. ofwater and the separated product was extracted with ether. The ethersolution was dried over sodium sulfate and concentrated to dryness underreduced presure. The residue was washed with water and dried to give78.8 g. of ethyl o-chlorophenylpyruvate p-chlorophenyl hydrazone m.p.l23125 C. i

The ethyl u-(o-chlorobenzyl acetoacetate used as a startingmaterial inthis example was obtained as follows: To a mixture of 97.5 g. of ethylacetoacetate, 17.3 g. of metallic sodium and 370 ml. of absolute ethanolwas added dropwise 133 g. of o-chlorobenzyl chloride under refluxingcondition. Stirring was continued under refluxing condition for anadditional 10 hours. The reaction mixture was cooled and filtered. Thefiltrate was concentrated and distilled under reduced pressure to give138 g. of ethyl or (o-chlorobenzyl) acetoacetate, b.p. 140 C./0.35 mm.Hg.

EXAMPLE 6 3300, 1690, 1550, 1492 cmr ELEMENTARY ANALYSIS (FOR ounmolrNozPercent o H N or Calculated 04.25 4.00 4.41 11.18 Found 64.28 3.92 4.0411.32

EXAMPLE 7 To a solution of 100 ml. of cone. sulfuric acid in 900 ml. ofisopropanol was added 526.5 g. of ethyl oz-(O- fluorophenyl) a(p-chlorophenylazo) acetoacetate and then the mixture was heated underrefluxing condition for 4 hours with stirring. The reaction mixture wascooled and the precipitate was collected by filtration, washed withwater and dried to give 336 g. of ethyl5-chloro-3-(o-fluorophenyl)-indole 2 carboxylate, m.p. 180-l86 C.Recrystallization from ethanol the melting point was raised to 188-189C.

The following compounds were similarly prepared:

Methyl 3-(o-fluorophenyl)-5-chloro-indole-2-carboxy1ate,

ethyl 3-(o-chlorophenyl)-5-chloro-indole-2-carboxylate,

tertiary butyl 3-(o-fiuorophenyl)-5-chloro-indole- Z-carboxylate,

benzyl 3-(o-fiuorophenyl)-5-chloro-indole-Z-carboxylate,

ethyl 1-cyclopropylmethyl-3-(o-fiuorophenyl)-indole- 2-carboxylate,

methyl1-cyclopropylmethyl-3-(o-fiuorophenyl)-5-chloroindole-2-carboxylate,

ethyl1-cyclo'propylmethyl-3-(o-fiuorophenyl)-5-chloroindole-Z-carboxylate,

tertiary butyl 1-cyclopropylmethyl-3-(o-chlorophenyl)-5-chloro-indole-2-carboxylate,

benzyl1-cyclopropylmethyl-3-(o-fiuorophenyl)-5-chloroindole-Z-carboxylate,

ethyl1-cyclopropylmethyl-3-(o-fiuorophenyl)-5-bromoindole-2-carboxylate,

ethyl1-cyc1opropylmethyl-3-(o-fluorophenyl)-5-fiuoroindole-Z-carboxylate,

methyl 1-cyclopropylmethyl-3-(o-fiuorophenyl)-6 (or 4)-chloro-indole-Z-carboxylate,

ethyl1-cyclopropylmethyl-3-(o-fiuorophenyl)-7-chloroindole-Z-carboxylate,

ethyl 1-cyclobutylmethyl-3-(o-fluorophenyl)-5-chloro- Iindole-Z-carboxylate,

ethyl1-cyclopentylmethyl-3-(o-fluorophenyl)-5-chloroindole-Z-carboxylate, and

ethyl 1-cyclohexylmethyl-3-(o-fluorophenyl)-5-chloroindoleQ-carboxylate.

EXAMPLE 8 A mixture of 78.8 g. of ethyl o-chlorophenylpyruvatep-chlorophenylhydrazone and 600 ml. of ethanol was heated to 70 C. intoa solution. Dry hydrogen chloride gas was introduced to the solution for1 hour below 70 C. with intermittent cooling. Stirring was continued at50 C. for an additional 1 hour. After cooling, the precipitate formedwas collected by filteration, washed with cold ethanol and then water,and dried to give 70.1 g. (93.4%) of ethyl5-(o-chlorophenyl)-indole-2-carboxylate, m.p. 195-196 C. The analyticalsample was recrystallized from ethanol, m.p. 196196.5 C.

EXAMPLE 9 A mixture of 25.6 g. of p-chloroaniline, 64 ml. of cone.hydrochloric acid and 90 ml. of water was heated to a solution and thencooled at C. To the mixture was added dropwise a solution of 13.9 g. ofsodium nitrite in 29.6 ml. of water below C., with stirring. Afteraddition, 23.4 g. of sodium acetate was added to the mixture. Theresulting mixture was added dropwise to a chilled mixture of 50.9 g. ofethyl a-(O-ChlOIO-benZYl) acetoacetate, 200 ml. of methanol and 39.2 g.of'anhydrous potassium acetate below 0 C. The reaction mixture wasstirred for 3 hours below 5 C., and extracted with ether. The ethereallayer was dried over sodium sulfate and concentrated under reducedpressure to an oily substance, which wasdissolved in-240 ml. of ethanoland dry hydrogen chloride gas was introduced to the solution for min.The mixture was stirred at 50-60 C. for

2 hours and then cooled to 0 C. After allowing to stand overnight at 0C., the precipitates were collected by filtration, washed with coldethanol and then water, and dried to yield 40 g. of ethyl5-chloro-3-(o-chlorophenyl)- indole-Z-carboxylate, mp. 195 -196 C. Theanalytical sample was recrystallized from ethanol, m.p. 196- 196.5 C.Infrared absorption spectrum,

ELEMENTARY ANALYSIS (FOR C17Hl302NC12) The following compounds weresimilarly prepared:

3-(o-chlorophenyl)-5-chloro-indole-Z-carboxylic acid,

3-(o-bromophenyl)-5-chloro-indole-2-carboxylic acid,

3-(m-chlorophenyl)-5-chloro-indole-Z-carboxylic acid,

3- (p-chlorophenyl)-5-chloro-indole-2-carboxylic acid,

1-cyclopropylmethyl-3 (o-fluorophenyl) -indole-2- carboxylic acid,

ethyl 1-cyclopropylmethyl-3- (o-fluorophenyl)-indole-2- carboxylate,

1-cyc1opropylmethyl-3-(o-fluorophenyl)-5-chloro-indole- Z-carboxylicacid,

methyl1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloroindole-2-carboxylate,

ethyl1-cyclopropylmethyl-3-(ofluorophenyl)-5-chloroindole-Z-carboxylate,

tertiary butyl 1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloro-indole-2-carboxylate,

benzyl 1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloroindole-2-carboxylate,

ethyl1-cyclopropylmethyl-3-(o-fiuorophenyl)-5-bromoindole-2-carboxylate,

methyl 1-cyclopropylmethy1-3-(o-fluorophenyl)-6- (or 4)-chloro-indole-Z-carboxylate,

ethyll-cyclopropylmethyl-S-(o-chlorophenyl)-7-chloroindole-Z-carboxylate,

ethyl1-cycl0propylmethyl-3-(p-chlorophenyl)-5-chloroindole-2-carboxylate,

ethyl1-cyclobutylmethyl-3-(o-fiuorophenyl)-5-chloroindole-2-carboxylate,

ethyl 1-cyclopentylmethyl-3-(ofiuorophenyl)-5-chloroindole-2-carboxylate,

ethyl1-cyclohexylmethyl-3-(o-iluorophenyl)-5-chloroindole-Z-carboxylate,

methyl 1-methyl-3- (o-fluorophenyl) -5-chloro-indole-2- carboxylate,

1-ethyl-3- (o-fluorophenyl) -5-chloro-indole-2-carb oxy lic acid,

1-methy1-3-(o-chlorophenyl)-5-chloro-indole-2-carboxylic acid,

ethyl 1-n-propy1-3-(o-fluorophenyl)-5-chloro-indole-2- carboxylate,

1-methyl-3-(fiuorophenyl -S-bromo-indole-2-carboxylic acid,

1-methyl-3-(o-chlorophenyl)-indole-2-carboxylic acid,

methyl 3-(o-fluorophenyl)-5-chloro-indole-2-carboxylate,

1-isobutyl-3 o-fiuorophenyl) -5-chl0ro-indole-2- carboxylic acid.

EXAMPLE 1O A mixture of 14 g. of p-chlorophenylhydrazine, 18.2 g. ofo-fluorophenyl-pyruvic acid 300 ml. of acetic acid and 300 ml. of cone.hydrochloric acid was heated under refluxing condition for 1 hour. Thereaction mixture was concentrated under reduced pressure and dilutedwith water to give S-chloro 3 (o fluorophenyl) indole -2- carboxylicacid, m.p. 252254 C. (decomp.

The following compounds were similarly prepared:

3-(o-chlorophenyl)-S-chloro-indole-2-carboxylic acid,

3-(o-bromophenyl)-5-chloro-indole-2-carboxylic acid,

3-(o-fluorophenyl)-5-chloro-indole-Z-carboxylic acid,

3- (m-chlorophenyl) -5-chloro-indole-2-carb oxylic acid,

3-(p-chlorophenyl)-5-chloro-indole-2-carboxylic acid,

1-cyclopropylmethyl-3- o-fluorophenyl -indole-2carboxylic acid,

ethyl l-cyclopropylmethyl-Br-(o-lluorophenyl) -indole-2- carhoxylate,

1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloro-indole Z-carboxylicacid,

methyl 1-cyclopropylmethyl-3-(o-fluorophenyl)-S-chloroindole-Z-carboxylate,

ethyl1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloroindole-Z-carboxylate,

tertiary butyl l-cyclopropylmethyl-3-(0fluorophenyl)-5-chloro-indole-Z-carboxylate,

benzyl l-cyclopropylmethyl-3- (o-fluorophenyl)--chloroindole-Z-carboxylate,

ethyl1-cyclopropylmethyl-3-(o-fluorophenyl)-5-bromoindole-Z-carboxylate,

methyl 1-cyclopropylmethyl-3-(ofiuorophenyl)-6 (or 4)-chloro-indole-Z-carboxylate,

ethyl1-cyclopropylmethyl-3-(o-chlorophenyl)-7-chloroindole-Z-carboxylate,

ethyll-cyclopropylmethyl-3-(o-chlorophenyl)-5-chloroindole-2-carboxylate,

ethyll-cyclopropylmethyl-3-(o-bromophenyl)-5-chloroindole-Z-carboxylate,

ethyll-cyclopropylmethyl-Bl-(m-chlorophenyl)-5-chloroindole-Z-carboxylate,

ethyll-cyclopropylmethyl-Za-(p-chlorophenyl)-5-chloroindole-Z-carboxylate,

ethyl l-cyclobutylmethyl-3-(o-fluorophenyl)-5-chloroindole-Z-carboxylate,

ethyll-cyclopentylrnethyl-3-(o-fluorophenyl)-5-chloroindole-Z-carboxylate,

ethyl1-cycloheXylmethyl-3-(o-fluorophenyl)-5-chloroindole-2-carboxylate,

methyl 1-n1ethyl-3- (ofiuorophenyl) -5-chloro-indole-2- carboxylate,

1-ethyl-3 (o-fluorophenyl) -5-chloro-indole-Z-carboxylic acid,

1-methyl-3- (o-chlorophenyl) -5-chloro -indole-2-car boxylic acid,

methyl l-n-propyl-3- (o-fluorophenyl -5-chlor0indole-2- carboxylate,

1 -methyl-3 (o-fiuorophenyl) -5-hromoindole-2-carb oxylic acid,

1-methyl-3- (o-chlorophenylindole)-2-carboxylic acid,

methyl 3-(o-fluorophenyl)-S-chloroindole-2-carboxylate and 1-isobutyl-3(o-fluorophenyl) -S-chloroindole-2-carboxylic acid.

EXAMPLE 11 To a mixture of 43 g. of ethyl5-chloro-3-(o-fiuorophenyl)-indole-2-carboxylate, 20 g. of potassiumhydroxide, 20 ml. of water and 100 ml. of acetone was added dropwise 26g. dimethyl sulfate below 60 C. The mixture was stirred at roomtemperature for 1 hour. The solvent was removed under reduced pressureto an oil. The oily residue was Washed with water and triturated withethanol to give 44 g. of ethyl1-methyl-5-chloro-3-(ofluorophenyl)-indole-2-carboxylate, m.p. 75 C. Asample of said compound was recrystallized from ethanol, m.p. 76 C.

This procedure was utilized to prepare the following compounds.

methyl l-methyl-3-(o-chlorophenyl)-5-chl0ro-indole-2- carboxylate,

methyl 1-methyl-3- (o-fluorophenyl)-5-chloro-indole-2- carboxylate,

ethyl 1-methyl-3-(o-bromophenyl)-5-chloro-indole-2- carboxylate,

ethyl 1-methyl-3-(o-chlorophenyl)5-chloro-indole-2- carboxylate,

ethyl l-methyl-3-(m-chlorophenyl)-5-chloro-indole-2- carboxylate,

ethyl 1-methyl-3-(p-ehlorophenyl)-5-chloro-indole-2- carboxylate,

ethyl 1-methyl-3-(o-fiuorophenyl)-5-chloro-ind0le-2 carboxylate,

benzyl 1-methyl-3-(o-fluorophenyl)-5-chloro-indole-2 carboxylate, '7

ethyl 1-ethyl-3-(o-fluorophenyl)-S-chloro-indole-2- carboxylate,

ethyl 1-propyl-3-(o-fluorophenyl)-5-chloro indole-2 carboxylate, w

ethyl 1-methyl-3-(o-fluorophenyl')-6 (or'4)-chloro-indole-Z-carboxylate,

methyl 1-methyl-3- (o-chlorophenyl) 'l chlor'o indoleri i i carboxylate,r M ethyl 1-methyl-3-(o-chlorophenyl) 5-bromo-indole-2- carboxylate, vethyl 1-methyl-3- (o-chlorophenyl)-5-fluoro-indo1e-2- carboxylate,

ethyl 1-cyclopropylmethyl-3- (o-chlor ophenyl -ind ole-Z- carboxylate,methyl 1-cyclopropylmethyl-3-(o-fluorophenyl)-5-chloroindole-Z-carboxylate, v ethyl 1-cyclopropylmethyl-3-(o-fluorophenyl)5-chloroindole-Z-carboxylate,

benzyl l-cyclopropylmethyl-3- (o-fluorophenyl)S-chloroindole-Z-carboxylate, ethyll-cyclopropylmethyl-Ia-(o-fluorophenyl)-5-hromoindole-2-carboxylate,ethyl l-cyclopropylmethylfi-(m-chlorophenyl):S-chloro:

indole-Z-carboxylate,

ethyl l-cyclopropylmethyl-3-(p-chlorophenyl)-5-chloroindole-carboxylate, ethyl1-cyclobutylmethyl-3-(o-fiuorophenyl)-5-chl0roindole-Z-carboxylate and Vethyl l-cyclopentylmethyl-3-(o-fluorophenyl)-5-chloro aindole-Z-carboxylate.

EXAMPLE l2 A mixture of 48 g. of ethyl5'-chloro-3-(o-fluorophenyl)-indole-2-carboxylate, 1.8 g. of potassiumhydroxide 3440, 2700-2300 (broad), 1680, 1555, 1490 cm? EXAMPLE 13 v Toa solution of 19 g. of potassium hydroxide in 350 ml. of methanol wasadded 45.9 g. of ethyl 5-chloro-3- (o fluorophenyl)-indole-2-carboxylateand the mixture was refluxed for 5 hours. The solvent was removed un'der reduced pressure and the residue was dissolved in 400 m1. of water.The solution was treated with charcoal, and

made acidic with cone. hydrochloric acid to give 40.1 g. of5-ch1oro-3-(o-fluorophenyl)-indole-2-carboxylic acid.

EXAMPLE 14 To a solution of 13.2 g. of potassium hydroxide in'300 ml. ofethanol was added 33.4 g. of ethyl5-chloro-3-(ochlorophenyl)-indole-2-carboxylate and the mixture was"refluxed for 2 hours. The solvent was removed under reduced pressure andthe residue was dissolved in 350 m1. of water. The solution was cooledto 0 C. and made acidic (pH 1) with 19 mlpof conc. hydrochloric acidunder cooling. The mixture was stirred at 0 C. for 1 hour and theprecipitate which formed was collected by filtration, washed thoroughlywith water, and dried to give 27.6 g. (90.3%) of5-chloro-3-(o-chlorophenyD-indole 2-carboxylic acid, m.p. 212213.5 C.(decomp.). The analytical sample was recrystallized frombenzene-ethanol,-

m.p.-215.5 216 (decomp.). Infrared absorption spectrum, I

m, 3415, 2550, 1676 cm.-

3-(o-chlorophenyl)-indole-2-carboxylic acid, 3(o-fluorophenyl)-indo1e-2-carboxylic acid,3-(m-chlorophenyl)-5-chloro-indole-Z-carboxylic acid,3-(p-chlorophenyl)-5-chloro-indole2-carboxylic acid and3-(o-fluorophenyD-6 (or 4)-chloro-indole-Z-carboxylic acid.

EXAMPLE 15 A mixture of 23.5 g. of -chloro-3-(o-fluorophenyl)-indole-2-carboxylic acid, 50 ml. of acetone, 18.2 g. of potassiumhydroxide and 18 ml. of water was heated into a solution. To the cooledmixture was added dropwise 20.5 g. of dimethylsulfate below 50 C. withstirring. The resulting mixture was heated under refluxing condition for4 hours. After completion of the reaction, the solvent was removed bydistillation, and the residue was dissolved in 200 ml. of water. Thesolution was treated with charcoal, and made acidic with conc.hydrochloric acid under cooling. The yellow precipitate which formed wascollected by filtration, washed thoroughly with water and dried to give24 g. (97.6%) of.1-methyl-5-chl0ro-3-(o-fluorophenyl)indole-2-carboxylicacid, m.p. 215.5-216 C. (decomp.). The analytical sample wasrecrystallized from methanol, m.p. 228 C. (decomp.).

.ELEMENTARY ANALYSIS (FOR CmHuOzNClF) Percent C H N Calculated 63. 27 3.65 4. 61 Found 63. 25 3. 88 4. 51

The following compounds were similarly prepared:

A mixture of 42.5 g. of ethyl1-methyl-5-ch1oro-3-(ofiuorophenyl)-indo1e-2-carboxy1ate, 16.6 g. ofpotassium hydroxide and 400 ml. of ethanol was refluxed for 2.5 hours.The solvent was removed under reduced pressure and the residue wasdissolved in 200 ml. of water. The cooled solution was made acidic with50 ml. of cone. hydrochloric acid under cooling. The precipitate whichformed was collected by filtration, Washed with water and dried to give37.7 g. of 1-methyl-5-chloro-3-(o-fluorophenyl)-indole-2-carboxylicacid, m.p. 218 C. The infrared absorption spectrum of this product wasidentical with that of product obtained in Example I 14.

The following compounds were similarly prepared:

1-methyl-3-('o-chlorophenyl)-5-chloro-indole-2-carboxylic acid,'- Y

1-methyl-3- (o-bromophenyl) -5 -ch1oroindole-2-carb oxylic acid, A

-1-methyl-3- (o-fluorophenyl -in'dole-2-carboxylic acid,

1-ethyl-3-(o-fluorophenyl)-5-chloro-indole-2-carboxylic acid, I I

1-cyclopropylmethyl-3- (o-fluorophenyl -5-bromo-indole- 2-carboxylicacid, 1

1-cycl0propylmethyl-3-(o-fluorophenyl)-6 (or4)-chloroindole-2-carboxylic acid, a

l-cyclopropylmethyl-3- (o-fluorophenyl) -5-chloro-indole-2-carboxylic'acid, I

1-cyclopropylmethyl-3- (o-fluorophenyl) -indole-2-carb0x- .ylic acid,

1-cyclobutylmethyl-3-(o-fluorophenyl)-5-chloro-indole-2- carboxylicacid,

1-cyclobutylmety1-3- (o-fluorophenyl -5-bromo-indole-2- carboxylic acid,

1-cyclopentylmethyl-3-(o-fluorophenyl)-5-chloro-indole-2- carboxylicacid and 1-cyclohexylmethyl-3- (o-fluorophenyl -5-chloro-indole-2-carboxylic acid.

EXAMPLE 17 A mixture of 30 g. of5-chloro-3-(o-fluorophenyl)-indole-2-carboxylic acid and 50 ml. ofthionyl chloride was heated under refluxing condition for 2 hours. Aftercompletion of the reaction, excess thionyl chloride was removed bydistillation. The yellowish residue was dissolved in 600 ml. of dryether and gaseous ammonia was introduced to the solution for 2 hourswith stirring under cooling. The precipitate formed was collected byfiltration, washed with water and dried to give 19.7 g. of 5- chloro 3(o-fluorophenyl)-indole-2-carboxamide, m.p. 2l3-214 C. The second cropwas obtained from the filtrate. Total yield was 27 g. The analyticalsample was recrysatllized from tetrahydrofuranbenzene, mp. 227 -228 C.Infrared absorption spectrum,

Paraffin.

v,,... 3460, 3300, 3200, 1659, 1592, 14.90 cmr ELEMENTARY ANALYSIS (FORCrsHroClFNzO) Percent Calculated 9. 71 12. 31 Found 9. 84 12. 23

EXAMPLE 18 EXAMPLE 19 A mixture of 18.2 g. ofl-methyl-S-chloro-3-(o-fluorophenyl)-indole-2-carboxylic acid and 29 g.of thionyl chloride was heated under refluxing condition for 2 hours.After completion of the reaction, excess of thionyl chloride was removedby distillation to obtain an oily residue to which was added 200 ml. ofdry toluene. Gaseous ammonia was introduced to the mixture underice-cooling with stirring. The precipitate which formed was collected byfiltration, washed with water and dried to give 11 g. (60.7%) of1-methyl-5-chloro-3-(o-fluorophenyl)-indole- 2-carboxamide, m.p. 159161C. From the filtrate, the second crops 1.4 g., 7.7%) was obtained, m.p.-156 C. The analytical sample was recrystallized from ethanol, m.p. 160C.

ELEMENTARY ANALYSIS (FOR CmHnClFNzO) Percent Calculated 63.48 4.00 9.2511.71 Found 63. 14 4. 02 '9. 00 11. 60

EXAMPLE 20 27 hour. The precipitate which formed was collected byfiltration, washed thoroughly with water and dried to give 27.7 g. of 5chloro-3-(o-chlorophenyl)-indole-2-carboxamide. Recrystallization fromethanol gave 21 g. of the product having m.p. 210212 C. Infraredabsorption spectrum,

v5.3: 3460, 3290 (shoulder), 3200, 1650, 1590 cm.

ELEMENTARY ANALYSIS (FOR omnmonmo The following compounds were similarlyobtained:

3- (o-fluorophenyl) -indole-2-c arboxamide,

3- (o-fiuorophenyl -S-bromo-indole-Z-carboxarnide,

3- (o-bromophenyl -5-chloro-indole-2-carboxamide,

3-(p-chlorophenyl) -S-chloro-indole-Z-carboxamide,

3- (m-chlorophenyl -5-chloro-indole-2-carboxamide,

3- o-fiu orophenyl -6 (or 4) -chloro-indole-2- carboxamide,

1 -cyclopropylrn ethyl-3 o-chlorophenyl -5-chloro-indole- 2-carboxamide,

1-cyclopropylmethyl-3- (o-fluorophenyl) -S-brmo-indole- Z-carboxamide,

l-cyclo pro pylmethyl-3 -'(o-fluoro phenyl -chloro-indole-2-carboxamide,

l-cyclopropylmethyl-B- (o-fluorophenyl) -6 (or 4) -chloroindole Z-carboxamide,

1-cyc1opropylmethyl-3- (o-fiuorophenyl -7- chloroindole-Z-carboxamide,

1-cyclobutylmethyl-3 -(o-fluorophenyl) -5-chloro-in d ole-2-carboxamide,

1-cyclo glentylmethyl -(o-fluorophenyl -5-chloro-indole- Z-carboxamide,

1-cyclohexylmethyl-3 (odluorophenyl) -5-chloro-indole- Z-carboxamide,

l-cyclohexylmethyl-3 (o-fluorophenyl) -5-chloro-indole- 2-carboxamide,

1-cyclopropylmethyl-3 -'(o-fiuorophenyl) -5-chloro-indole- 2-hydroxamicacid,

1-methyl-3 (o-chlorophenyl) -5-chloro-indole-2-hydroxamic acid,

1 -methyl-3-'(o-fluorophenyl) -5-bromo-indole-2-c arboxamide,

'1 -methyl-3- (o-tluorophenyl) -5-fluoro-indole-2-carboxamide andl-ethyl-B- (o-fluorophenyl) -5-chloro-indo1e-2-carboxamide.

EXAMPLE '2 1 A mixture of 4.35 g. of 5-chloro-3-(o-fluorophenyl)-indole-Z-carboxylic acid and 7.2 g. of thionyl chloride was heated underrefluxing condition for 1.5 hours. After completion of the reaction,excess thionyl chloride was removed to give5-chlor0-3-(o-fluorophenyl)-indole-2-carboxylic chloride as a yellowsolid. The product was further confirmed by the following process. Thatis, this crude acid chloride was dissolved in 100 ml. of dry ether, andgaseous ammonia was introduced to the mixture at 10 C. for 15 min. withstirring. Stirring was continued .for additional 1 hour at roomtemperature. The precipitate formed was collected by filtration, washedwith water and dried to give 3.92 g. of 5-chloro-3-(o-tluoro phenyl)indole -2-carboxamide. After recrystallization fromtetrahydrofuran-benzene, the product having rn.p. 2.27 -228 C.

EXAMPLE 2.2

A mixture of 27. 6 g. of 5-chloro-3-(o-chlorophenyl)-indole-Z-carboxylic acid and 32.2 g. of thionyl chloride was heatedunder refluxing condition for 2 hours. After completion of the reaction,excess of thionyl chloride was removed under reduced pressure. Theresidue was triturated with dry ether to yield5-chloro-3-(o-chlorophenyl)-indole-2-carboxylic chloride as a yellowsolid quantitatively.

The product was further confirmed by the following process, that is,this crude acid chloride was suspended in 1-50 ml. of dry ether, andgaseous ammonia was intruded to the mixture under cooling. Theprecipitate which formed was collected by filtration, washed thoroughlywith water and dried to give 5-chlor0-3- (o-chlorophenyl) indole2-carboxamide. Recrystallization from ethanol gave the product havingmp. 210-2 12 C.

The following compounds were similarly prepared:

3-(o-chlorophenyl)-indole-2-carboxylic chloride, 3-'(o-fluorophenyl)-indole-2-carboxylic chloride, 3-(p-chlorophneyl)-5-chloro-indole-2-carboxylic chloride, 3(o-fiuorophenyl)-5-chloro-indole-2-carboxylic bromide,3-(o-fluorophenyl)-5-bromoindole-Z-carboxylic chloride,3-(o-fluorophenyl)-5-fiuoro-indole 2-carboxylic chloride, 3-(o-fluorophenyl -5-chloroindole-Z-carboxylic bromide, 3(o-fluorophenyl)-indole-2-carboxylic bromide, 3-(o-fiuorophenyl)-6 (or4)-chloro-indole-2-carboxylic chloride, 3-(o-fluorophenyl)-7-chloro-indole-2-carboxylic chloride,l-methyl-B-(-o-chlorophenyl)-5-chloro-indole-Z-carboxylic chloride,"1-methyl-3-'(o-*fluorophenyl) -5-chloro-indole'2-carb oxylic chloride,1-ethyl-3- (o fiuorophenyl) -S-chloro-indole-2-carboxylic chloride, 11-cyclopropylmethy1-3-( o-zfluoro phenyl) -5-chloro-indole- 2-carboxylicchloride, l-cyclobutylmethyl-fi-(o-fluorophenyl)-5-chloro-indole-2-carboxylic chloride, 1-cyclopentylmethyl-3-(ofiuorophenyl)-5-chl0ro-indole- Z-carboxylic chloride andl-cyclohexylmethyl-3 (o-fluorophenyl)-5-chloro-indole- Z-carboxylicchloride.

To a mixture of g. of 5-chloro-34o-fluorophenyl)- indole-Z-carboxamide,50 g. of potassium hydroxide, 50 ml. of water and 250 ml. of acetone,was added dropwise 65 g. of dimethylsulfate below 40 C. The mixture wasstirred at room temperature for 30 min. The solvent was removed underreduced pressure. The residue was washed with water and dried to give99.1 g. of l-methyl-5-chloro- 3-(o-fluophenyl)-indole-2-carboxamide, mp.146 -156. Recrystallization from ethanol was repeated for an analyticalsample, m.p. 160 C. The infrared absorption spectrum of this product wasidentical with that of product obtained in Example 118.

The following compounds were similarly prepared:

1 -me thyl-3 o-chlorophenyl) -5-chloro-indole-2-carboxamide,

1-rnethyl-3-(o-fluorophenyl)-5-bromo-indole-2-carboxamide, 1-ethyl-3-(o-fiuorophenyl) -indole-2-carboxamide and1-cyclopropylmethyl-3-(o-fiuorophenyl)indole-2- carboxamide.

EXAMPLE 24 To a solution of 15 g. of 5-chloro-3-(o fluorophenyl)-indole-Z-carboxamide in 150 ml. of dimethylformamide was added 2.49 g.of 61.4% sodium hydride. The mixture was stirred at room temperature andthen at 50 C. for '1 hour. After cooling, 8.8 g. ofcyclopropylmethylbromide was added to the mixture. The resulting mixturewas heated at l00-120 C. for 4 hours. After the reaction was completed,400 ml. of water was added to the reaction mixture. The separated oilyproduct was extracted with ether and the ethereal layer was dried oversodium sulfate and the solvent was removed under reduced pressure togivel-cyclopropylmethyl-S-chloro-3-(o-liuorophenyl)-indole-2carb0xamide, asa yellow oily substance. This product was used in the next step withoutfurther purification The following compounds were similarly prepared:l-cyclo pro pylmethyl-3- (o-chlorophenyl) -indole-2-carboxamide,l-cyclopropylmethyl-il-(o-fiuorophenyl)-indole-2-carboxamide and1-cyclopropylmethyl-3-(o-chlorophenyl)-5-chloro-indole- 2-carboxamide.

EXAMPLE 25 EXAMPLE 26 To a suspension of 30.8 g. of lithium aluminumhydride in 3 l. of dry ether was added 81.7 g. of l-methyl-S-chloro-3-(o-fluorophenyl)-indole-2-carboxamide and the mixture wasrefluxed for 3 hours with stirring. To the cooled reaction mixture wasadded dropwise 200 ml. of water with stirring under cooling. To theethereal layer was added 150 ml. of cone. hydrochloric acid undercooling. The precipitate which formed was collected by filtration toyield 60.5 g. of 1-methyl-2-aminomethyl-3-(o-fiuorophenyl) 5chloro-indole-hydrochloride, m.p. 246 C. (decomp.).

ELEMENTARY ANALYSIS (FOR ClflHlENZChF) Percent Calculated 8. 61 21. 81Found 8. 53 21.91

EXAMPLE 27 To a suspension of 3.8 g. of lithium aluminium hydride in 40ml. of dry ether was added 5.25 g. of S-chloro-3-(o-chlorophenyl)-indole-2-carboxamide under cooling. The mixture wasstirred under refluxing condition for hours and then cooled to 0 C. Tothe reaction mixture was added dropwise 20 ml. of water under coolingwith stirring. The ethereal layer was separated by decantation and theaqueous layer was washed with 150 ml. of ether. The combined ethereallayer was dried and concentrated to dryness to yield 3.75 g. of a yellowsolid, which was recrystallized from benzene gave 3 g. of 2-aminomethyl-5-ch1oro-3-(o-chlorophenyl)-indole, m.p. 145 -149.5 C.

The following compounds were similarly prepared:

2-aminomethyl-3- o-chlorophenyl-indole, 2-aminomethyl-3 (o-fluorophenyl-indole, 2-aminomethyl-3- o-chlorophenyl) -5chloro-indole,2-aminomethyl-3- (o-fluorophenyl) -5-bromo-indole,2-aminomethyl-3-(o-fluorophenyl)-6 (or 4)-chloroindole, 2-aminomethyl-3(o-fluorophenyl -7-chloro-indole, 1-methyl-2-aminomethyl-3-o-fluorophenyl) -indole,1-methyl-2-aminomethyl-3-(o-chlorophenyl)-indole,1-methyl-2-aminomethyl-3- (o-chlorophenyl) -5 -chloroindole, ll-ethyl-2-aminomethyl-3-(ofluorophenyl)-5-chloroindole,1-methyl-2-aminomethyl-3-(o-fluorophenyl)-5-bromoindole,1-methyl-2-aminomethyl-3- (o-fluorophenyl -5-chloroindole, a Y1-cyclopropylmethyl-2-aminomethyl-3 o-fluorophenyl) indole,

1-cycl0propylmethy1-2-aminomethyl-3 (o-fiuorophenyl) 5 -chloro-indole,1-cyclopropylmethyl-2-aminomethyl-3 (o-fiuorophenyl) 5 -bromo-indole,1-cyclopropylmethyl-2-aminomethyl-3- (o-chlorophenyl 6 (or 4-chloro-indole, 1-cyclopropylmethyl-Z-aminomethyl-3- o-bromophenylS-chloro-indole, 1-cyclobutylmethyl-2-aminomethyl-3 (o-fluorophenyl)5-chloro-indole, 1-cyclopropylmethyl-2-aminomethyl-3- o-fluorophenyl)S-bromo-indole, 1-cyclopropylmethyl-Z-aminomethyl-3 (o-fluorophenyl 5-fluoro-indole and their hydrochlorides, hydrobromides, sulfates,nitrates and phosphates.

EXAMPLE 28 A mixture of 20.7 g. of3-(o-fiuorophenyl)-5-chloroindole-Z-carboxamide and 107 g. ofphosphorous oxychloride was heated under refluxing condition for 20 min.After cooling, the reaction mixture was poured into 800 ml. of ice-waterand the mixture was neutralized with ammonium hydroxide. The resultingprecipitate was collected by filtration, washed with water and dried togive 18.7 g. of 5-chloro-3-(o-fiuorophenyl)-indole-2-carbonitrile, m.p.185 -186 C. Yield: 98.7%. Recrystallization from benzene raised themelting point to 187188 C. Infrared absorption spectrum,

Paraffin.

1 3300, 2220, 1546, 1492 emai ELEMENTARY ANALYSIS (FOR CISHBClFN?) Amixture of 15.3 g. of 5-chloro-3-(o-chlorophenyl)- indole-Z-carboxamideand 76.8 g. of phosphorous oxychloride was stired at C. for 20 min.After cooling, the reaction mixture was poured into 500 ml. ofice-water. After neutralization of the mixture with ammonium hydroxide.The precipitate was collected by filtration, washed thoroughly withwater and dried to give 13.7 g. (95.8%) of5-chloro-3-(o-chlorophenyl)-indole 2 carbonitrile, m.p. l66.5-167.5 C.Infrared absorption spectrum,

v 3315, 2230 cm.- ELEMENTARY ANALYSIS (FOR ClsHsNzCl) Percent C H N 01Calculated 62. 74 2. 81 9. 76 24. 69 Found 62. 92 2. 63 9. 55 24. 52

l-cy clobutylmethyl-3 (o-fluorophenyl) --chloro-indole- Z-carbonitrile,1-cyclopentylmethyl-3-(o-fiuorophenyl)-5-chloro-indole- 2-carbonitrileand l-cyclohexylmethy1-3-(o-fluorophenyl)-5-chloro-indo1e-Z-carbonitrile.

EXAMPLE 30 To a suspension of 2 g. of lithium aluminum hydride in 300ml. of dry ether, was added 3.52 g. of 5-chloro-3-(o-fluorophenyl)-indole-2-carbonitrile and the mixture was heated underrefluxing condition for 4 hours with stirring. After completion of thereaction, the reaction mixture was cooled with ice, and water was addeddropwise to the mixture with stirring to decompose excess lithiumaluminium hydride. The ethereal layer was separated, dried over sodiumsulfate and the solvent was removed by distillation under reducedpressure to give 3.3 g. (92.5%) of2-aminomethyl-3-(o-fluorophenyl)-5-chloro-indole, mp. 159 -161 C.Recrystallization from benzene-petroleum ether raised the melting pointto 162- 163 C. Infrared absorption spectrum,

ELEMENTARY ANALYSIS (FOR C1sHi-2C1FN'2) Percent C H N Calculated 65. 574. 37 10. 20 Found 65. 89 4. 20 9. 98

The following compounds were similarly prepared:

and their hydrochlorides, hydrobromides, sulfates, phosphates andacetates.

EXAMPLE 31 To a mixture of 5.2 g. of 5-chloro-3-(o-fluorophenyD-indole-2-carbonitrile, 18 ml. of acetone, 3.8 g. of potassium hydroxideand 38 ml. of Water was added dropwise 4.9 g. of dimethylsnlfate below50 C. Stirring was continued for an additional 30 min. and then theacetone was removed under reduced pressure. The residue was diluted withwater and filtered to give 5 g. of l-methyl-S- chloro-3 (o-fluorophenyl)-indole-2-carbonitrile.

This l-methyl-S-chloro-S-(o-fluorophenyl)-indole-2-carbonitrile wasadded to a suspension of 3 g. of lithium aluminum hydride in 400 ml. ofdry ether. The mixture was heated under refluxing condition for 5 hourswith stirring. After the reaction was completed, the reaction mixturewas cooled to 0 C. and water was added dropwise to the mixture withstirring to decompose excess 32 lithium aluminum hydride. The ethereallayer was separated and dried over sodium sulfate. To the ethereal layerwas introduced dry hydrogen chloride under cooling. The precipitatewhich formed was collected by filtration to give 1methyl-2-aminomethyl-3-(o-fluorophenyl)-5- chloro-indole hydrochloride,m.p. 246 C. (decomp).

EXAMPLE 32 A solution of 3 g. of chromic anhydride in 3 ml. of water wasadded dropwise to a solution of 2.9 got 2- aminomethyl-5-chloro3-(o-chlorophenyl)-indole in '20 ml. of acetic acid. The mixture wasstirred at room temperature for 26 hours. To the reaction mixture wasadded 10 ml. of water and then 50 ml. of 28% ammonium hydroxide withstirring under cooling. The resulting'rnixture was extracted withchloroform and the organic layer was dried and concentrated underreduced pressure. The, residue was purified by chromatography on silicagel to give 7-chloro-5-(o-chlorophenyl) 1,3 dihydro-2H-1,4-benzodiazepine-Z-one, m.p. 199-201 C.

EXAMPLE 33 A solution of 40 got chromic anhydride in 30 ml. of water wasadded dropwise to a suspension of 40 g. of2-aminomethyl-5-chloro-3-(o-fluorophenyD-indole hydrochloride in 400 ml.of acetic acid at 157-20 C. The mixture was stirred at room temperatureovernight. The reaction mixture was added dropwise to a mixture of 850ml. of 28% ammonium hydroxide, 850 m1. of water and 700 ml. of methylenechloride with stirring under cooling. The aqueous layer was separatedand extracted with methylene chloride. The organic layer was combinedand concentrated in vacuo. The residue was triturated with benzene, andthen filtered, washed with benzene and dried to give 18 g. of crudeproduct which was taken up with ethanolic hydrogen chloride to yield 4.5g. of 7-chloro-5- (o-fluorophenyl) 1,3 dihydro-ZH-1,4-benzodiazepine-2--one hydrochloride, m.p. 235 C. (decomp).

The filtration and washing were combined and evaporated in vacuo. To theresidue was added toluene and the mixture was heated under refluxingcondition. The solvent was removed in vacuo and the residue was Washedwith ethanol to give 12 g. of crude product, which was treated withethanolic hydrogen chloride to yield 11.5 g. of7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-Z-onehydrochloride, mp. 236 C. (decomp).

This hydrochloride was treated with ammonium hydroxide, and thenextracted with chloroform. The solvent was removed in vacuo to yield 8.3g. of free 7-chloro-5- (ofluorophenyl)-1,3dihydro-2H-1,4-benzodiazepine-2-one, m.p. 202203 C. Recrystallizationfrom ethanol raised the melting point to 204-205 C. Infrared absorptionspectrum,

Penmav 1690, 1618 cm? ELEMENTARY ANALYSIS (FOR Ci5H1uN2OC1F) Percent C HN Calculated 62. 40 3. 49 9. 70 onnd 62. 54 3. 38 9. 43

EXAMPLE 34 ELEMENTARY ANALYSIS (FOR C19Hl6N2OClF) Percent v H NCalculated s. 61. 57 4.70 8.17 Found 6 1.42 I 4. 53 8. 04

- EXAMPLE I 35 A solution of 60 g. of chromic anhydride in 40 ml. ofwater-was added dropwise to a suspension of 60 g. of 2 aminomethyll-methyl--chloro-3-(o-fluorophenyl)- indolehydrochloride in 600 ml. ofacetic acid. The mix- .ture was stirred at room temperature overnight.To the reaction mixture was added 1.1 1. of ether and 1 l. of water and:then 800 ml. of 28% ammonium hydroxide, in small portions. The ethereallayer was separated, washed with water, dried and concentrated underreduced pressurea'The residue (51.8 g.) was dissolved in 100 m1. ofethanol, and 100ml. of 20% ethanolic hydrogen chloride was added to thesolution and the mixture was cooled. The precipitate was collectedbyfiltration to yield 46.5 g. Of 1methyl-7-chloro5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one hydrochloride, m.p. 218 C. (decomp.).Recrystallization from ethanol raised the melting point to 218.5219 C.(decomp.).

I ELEMENTARY ANALYSIS (Ft) R CisHiaNzoClF-Hcl) Percent Calculated 56. 65s. 26 Found 56. 72 3. 1a

5 (o-chlorophenyl -1,3-dihydro-2H-1,4-benzodiazepine- 2'-one,

5- (o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine- 2-one,

5- (0-chlorophenyl)-7-chloro-l,3-dihydro-2H-l,4-benzodiazepine-Z-one,

5-(o-bromophenyl)-7-ch1oro-1,3 dihydro-2H-lA-benzodiazepine-2-one,

5- (m-chlorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiaZepine-2-one,-

S-(p-chlorophenyl) -7-bromo-l,3-dihydro-2H-1,4-benzodiazepine-Lone,

1-methyl-5- (o chlorophenyl) -7-chloro-1, 3-dihydro-2H-'1,4-benzodiaiepine-2one,

l-methyl-j o-flu orophenyl) -7-chlorol ,3-dihydro-2H-1,4-benzodiazepine-Z-one,

l-methyl-S- (o-fluorophenyl) -7-bromo-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

l-ethyl-S- o-fluorophenyl) -7-chloro-1,3dihydro-2H-1,4-benzodiazepine-2-one,

1-propyl5-(o-fiuorophenyl)-7-chloro-l,3-dihydro-2H-1,4-benzodiazepine-2-one,

1-cyclopropylmethyl-5- (o-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2-one,

l-cyclopropylmethyl-S-(o-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-0rie,

l-cyclopropylmethyl-S-(o-fiuorophenyl)-7-chloro-1 ,3-

dihydro-ZH-l,4-benzodiazepine-2-one,

l-cyclopentylmethyl-S-(o-fiuorophenyl)-7-chloro-1,3-

dihydro-ZH-l,A-benzodiazepine-Z-one,

l-cyclopropylmethyl-S-(o-chlorophenyl)-7-chlor0-1,3-

dihydro-ZH-1,4-benzodiazepine-2-one,

l-cyclopropylmethyl-S-(o-fluorophenyl)-9-chloro-1,3-

dihydro-ZH-1,4-benzodiazepine-2-one,

l-cyclopropylmethyl-S-(o-fluorophenyl)-7-bromo-1,3-

dihydro-ZH-1,4-benzodiazepine-2-one,

1-cyclobutylmethyl-5-( o-fiuorophenyl)-7-chloro-1,3-

dihydro-ZH-1,4-benzodiazepine-2-one, l-cyclopentylmethyl-S-(o-fiuorophenyl) -7-bromo- 1,3-

dihydro-2H-1,4-benzodiazepine-2-one and l-cyclohexylmethyl-S-(o-fluorophenyl)-7-chloro-1,3-

dihydro-ZH-1,4-benzodiazepine-2-one.

We claim:

1. A process for preparing a benzodiazepine represented by the formula,

i g [I] wherein R is a hydrogen atom, an alkyl group having 1 to 3carbon atoms or a cycloalkylmethyl group having 4 to 7 carbon atoms, andR is a hydrogen atom or a halogen atom, and X is a halogen atom whichcomprises reacting in the presence of a solvent a Z-aminomethyl indolerepresented by the formula,

benzodiazepine represented by the formula,

wherein R is a hydrogen atom, an alkyl group having 1 to 3 carbon atomsor a cycloalkylmethyl group having 4 to 7 carbon atoms and R is ahydrogen atom or a halogen atom and X is a halogen atom, which comprisesreacting in the presence of a solvent a 2-aminomethyl indole representedby the formula,

Q N/ CH2NHI wherein R R and X respectively have the same meanings asdefined above, or acid addition salt thereof with at least thestoichiometric amount of an oxidizing agent selected from the groupconsisting of ozone, hydrogen peroxide, peracids, chromic acid andpotassium permanganate, to yield the benzodiazepine of the formula 35[I] and reacting the benzodiazepine of the formula [I] with a mineral ororganic acid to yield the acid addition salt thereof.

3. The process according to claim 1 wherein said peracids are selectedfrom the group consisting of performic acid, peracetic acid andperbenzoic acid.

4. The process according to claim 2 wherein said peracids are selectedfrom the group consisting of performic acid, peracetic acid andperbenzoic acid.

5. The process according to claim 2 wherein said mineral acid isselected from the group consisting of hydrochloric acid, sulfuric acid,nitric acid and phosphoric acid and said organic acid is selected fromthe group consisting of maleic acid, fnmaric acid, succinic acid, formicacid, and acetic acid.

References Cited UNITED STATES PATENTS 3,192,199 6/1965 McMillan et al.260-2393 D 3,221,050 11/1965 McMillan et al. 260-2393 D 3,284,503 11/1966 McMillan et al. 260-2393 D 3,144,439 8/1964 Reeder et al. 260-23933,192,200 6/1965 Wuest 260-2393 3,371,085 2/1968 Reeder et al. 260-2393D 3,558,603 1/ 1971 Yamamoto et al. 260-2393 D FOREIGN PATENTS 846,5608/1960 Great Britain 260-2393 D 36 OTHER REFERENCES I Elderfield,Heterocyclic Compounds, vol. 3, pp. 8--

13 (Wiley) (1952). I

Noller, Chemistry of Organic Compounds, 2nd ed., pp. 250 and 254(Saunders) (1957). 7

Chemical Abstracts, v01. 52 (1958), cols. 11039.-

Abstracting Nogradi, Monatsh. Chem, vol. 88, pp. 1087-94 1958).

Sternbach et al., Some Aspects of Structure-Activity Relationship inPsychotropic Agents of the 1,4-Benzodiazepine Series, a symposium heldat the Regional Research Laboratory, Hyderbad, India, CSIR, New Delhi,India (1966).

Doyle et al., J. Chem. Soc., (1956), 2853-2857.

Nogradi Monatschefte fiir Chemie, Band 88 (1957), pp. 1087-4094.

Guyer et al., Helvetica Chim Acta, vol. 38, pp. 1649'- 1654.

IWojcik et al., Jacs, vol. 56, pp. 2419-2424 (1934).

HENRY R. 11125, Primary Examiner R. T. BOND, Assistant Examiner U.s..c1. X.R.

